Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review

Abstract

Solubility limited bioavailability is one of the crucial parameters that affect the formulation development of the new chemical entities. Thus the major constraint in the pharmaceutical product development is the suitable solubility enhancement technique for Active Pharmaceutical Ingredient. Solid dispersion (SD) is an established and preferred method for improving the solubility which ultimately may be helpful to enhance bioavailability. For long period of time Amorphous solid dispersion (ASD) have been preferred for improving solubility, but since last two decades, ASD approach have been combined with different modified release approaches to improvise the stability and site specificity of SD to grasp a hold over the specific advantages associated with such dosage forms. It is an established fact now that the SD technique not only improves solubility limited bioavailability, but it may be combined with other approaches to modify the drug release profile from the formulation as per the requirement based on the apt selection of SD carriers and suitable technology. This review covers the comprehensive overview of all such formulations where SD technology is used to serve dual purpose rather than only the sole purpose of solubility enhancement. The SD approach has been successfully implemented for some of the poorly soluble herbal drugs and still there is a vast scope of advancement in that area. The current review will provide a broad outcome in the area of SD technology for modified release formulations along with the description of current status and future prospective of SD.

Graphical abstract

The SD formed by dispersing drug within the conventional carrier to form ASD increases solubility, dissolution rate and bioavailability; whereas fourth generation hydrophobic carriers provide added advantage of controlled release (CR) or sustained release (SR) profile along with enhanced stability of SD. On the other frontier, pH dependant carriers enable the SD to achieve site specificity or delayed release (DR) profile.

Introduction

Oral route of administration is the most widely used and suitable route, with solid oral dosage forms being widely used over other types of dosage forms because of their smaller size, good stability, dose uniformity, and easy manufacturing [1]. Solubility is one of the significant parameters that affect the bioavailability of formulation [2]. According to the statistics, about 40% of currently available drugs and 60% of compounds undergoing synthesis are poorly soluble in water and face bioavailability problem [3]. Dissolution is one of the prominent problems faced by the compounds during the development phase [4]. Therefore, the major constraint for formulation scientist is to find an efficient approach to enhance the solubility of the API (Active Pharmaceutical Ingredient) to increase the dissolution rate of formulation [5, 6].

Solid dispersion is one of the preferred methods to overcome solubility limited bioavailability of API with low aqueous solubility [7–10]. Solid dispersion is a solid matrix made up of at least two components: Poorly soluble drug and SD carrier mostly hydrophilic in nature [11]. It is also possible to design multi-component SD wherein more than two components are used to improve formulation as well as therapeutic efficacy simultaneously [12]. Ternary SD consisting of surfactant shows significant improvement in drug dissolution [13]. The drug can be dispersed molecularly in a crystalline or amorphous carrier to enhance dissolution [14, 15]. The drugs can even exist in their amorphous forms which are theoretically the highest energetic solid state of a material and hence have the advantage in terms of apparent solubility [16]. Amorphous solid dispersion (ASD) not only improves rate and extent of dissolution, but also stabilizes the formulation using polymer matrix [17–19]. ASD provides super saturation for longer period of time enabling higher dose incorporation of poorly soluble drugs in the formulation [20, 21].

The selection of suitable SD carrier to achieve the desired type and physics of SD is extremely important. There is a wide range of SD carriers as explained in Fig. 1 [22, 23]. Recently many novel polymers have been researched and extensively used in SD Technology. The most widely used amphiphilic cellulosic SD carrier is HPMC-AS. The block graft copolymer Soluplus® is SD carrier of choice due to excellent solubilization, extrudibilty as well as stabilization properties [24]. Copovidone (PVP VA64) is also a versatile SD carrier preferable for both HME and Spray Drying techniques due to low glass transition temperature and good solubility in both polar and nonpolar solvents [25]. kollidon 12PF is a low molecular grade soluble povidone used as solubilizer, dispersing agent and crystallization inhibitor in SD preparation [26]. Kollicoat® Smartseal has also proved to be an excellent SD carrier along with taste masking and hygroscopic properties [27].

Fig. 1.

Carriers available for SD

There is a wide range of methods available to enhance the solubility of API namely nano-particle based formulations, lipid-based formulations, SD Technology, Reduction in particle size, salt formation or use of prodrug [28]. Out of the wide option of methods available, SD is one of the favored methods to increase solubility of drug. [29]. The physicochemical characteristics of the API and the SD carrier as well as the preparation method used have a crucial role in deciding the type and characteristics of SD formed. Thus the selection of suitable technique to prepare SD and optimization of the process parameters is significant to achieve desirable formulation characteristics [30]. The different methods used to prepare SD [2, 31–33] are summarized in Fig. 2. The extensively used and preferred techniques in SD development are HME, Spray Drying, Co-precipitation and Supercritical Fluid [34, 35].

Fig. 2.

Manufacturing techniques for SD

The SD technique was initially invented to enhance the in-vitro drug release rate and the bioavailability of drugs with poor aqueous solubility by using hydrophilic carriers for entrapping the drug [36]. But recently, hydrophobic and hydrophilic swellable polymers are also preferred as SD carrier to retard the dissolution of drug for the designing of controlled or sustained release formulations. [37]. Controlled release SD bypass the risk of a burst release of drug due to dispersion of drug molecules in carrier/s that lead to desired release rate [38]. The main limitations observed in CR SD are the Pilot plant scale up and commercial viability of product even after extensive research [39]. Different SD carriers and preparation methods are being explored to develop CR SD. The different carriers used to prepare CR SD are EC, HPMC, HPC, HPMCP, different grades of Eudragit and others [40, 41].

CR SD aims to serve dual benefits of sustained as well as controlled release dosage forms for low aqueous soluble drugs by providing an immediate dose followed by a maintenance dose to acquire a desired value of C_ss (steady state plasma concentration) over elongated period of time [42]. CR formulations offer many significant advantages compared to the conventional immediate release dosage forms, like the constant and prolonged therapeutic effect along with the improvement in patient compliance due to less number of doses per day and minimized adverse effects. [43]. SD may be preferred to improve the dissolution rate of drugs with low aqueous solubility and to prolong the drug release rate by selection of a suitable carrier [44]. CR and SR systems have gained popularity in the treatment of diseases because they maintain the therapeutic effect for an appropriate extended time by allowing the drug to release at the desired site of choice at a constant rate [45]. The recent research pertaining to CR systems is mainly based on drug candidates with low aqueous solubility which leads to inadequate properties, such as reduction in dissolution rate, absorption rate and decreased bioavailability [46].

Even though solid dispersions have proven to be an efficient technique, the development of specific dosage form consisting of SD is equally challenging to enhance the solubility as well as bioavailability of drugs with poor water solubility [47, 48]. Solid dispersions are widely used in different solid dosage forms like powders, granules, capsules, tablets, pellets or films with the purpose of improving solubility and the dissolution rate [49–51]. Hence to improve in-vivo behaviour of these solid dosage forms, it is required to develop solid dispersions in certain scenario. The preparation methods and release mechanisms of SDs have been explored in various studies. The suitable formulations necessary to complement the constant release of low aqueous soluble drugs from SD have been investigated to improve the bioavailability and therapeutic applications to further extent. Different formulations can be designed by incorporating SDs in suitable dosage form during or after the manufacturing of SD [52].

Modified Release (MR) dosage forms

MR dosage form is defined as the one formed by modifying the existing conventional formulation with respect to release rate, release time or site of release [53].

Modified release can be achieved by different release mechanisms as conveyed in Fig. 3.

1. Extended Release [ER, XR, XL]: The main purpose is reduction in dosing frequency through prolonging the drug release profile [38, 54].

   1. Sustained Release [SR]: SR formulation provide an IR (Immediate Release) dose for normal onset of action, followed by maintenance dose to sustain the Pharmacological effect for known desired prolonged period of time usually 8–12 h [55].
   2. Controlled Release [CR]: Release the drug at a predefined controlled rate, for a specific time duration, locally or systematically [38].

2. Delayed Release [DR]: DR formulation release the drug at any time other than immediately after administration as observed in IR formulations [56].

3. Targeted/ Site specific Release: The site specific formulation release the drug at a specific site in the body like colon, buccal cavity, stomach, etc. The targeted formulation is designed to release the drug at specific target at cellular or receptor level [57].

Fig. 3.

Types of Modified Release Dosage Forms

The modified release formulations overcome major limitations of IR formulations providing several advantages as described in Fig. 4.

Fig. 4.

Advantages of Modified Release DDS

This review is meant to summarize all the well known perspectives of modified release dosage forms consisting of solid dispersions, with special emphasis on the possible drug delivery systems, dosage forms and preparation methods.

Oral extended release drug delivery systems

Lu et al. worked on the development of oral CR formulation of gliclazide based on Spray Dried Dispersion technology. Gliclazide is BCS Class II drug belonging to 2^nd generation sulfonylurea category preferred for the treatment of type 2 diabetes. SDD of gliclazide were prepared using SD carriers HPMC-AS of H, M & L grades and copovidone S-630 in different ratios to convert the drug into amorphous form and render hydrophilicity to the formulation. The dispersions were evaluated for all the necessary physicochemical characterization parameters and were found to be in the required range. The saturation solubility and micro dissolution study of SDD were performed and compared with crystalline form of drug in FaSSIF pH 6.5 under non-sink conditions. The Solubility of drug improved by around 1.5 to 4 folds and the supersaturation state prevailed for longer period of time. The optimized SDD were incorporated within the matrix of HPMC using compaction simulator. During the in-vitro dissolution testing of the formulation using USP apparatus I under standard conditions, the drug showed varying rates of dissolution as predicted from the release kinetics study. The stability study showed similar dissolution profiles with similarity factor greater than 85 after six months. Hence, it was confirmed that HPMC-AS and copovidone were promising SD carriers to form stable and homogenous monophasic SDD that could be successfully loaded into hydrophilic CR matrix system of HPMC [58].

Keen et al. developed CR SD containing drugs Itraconazole and Carbamazepine using PVP as SD carrier and Compritol 888 as release modifying agent & plasticer by two different methods namely Holt melt extrusion and KinetiSol Dispersing.. The use of lipid carrier glyceryl behenate allowed convenient processing of high MW PVP during HME technology. The entrapment of drug in amorphous form within the SD was confirmed based on DSC, PXRD and thermal analysis. The compritol ratio was selected 1.5 parts in compressed tablet prepared from extruded SD and it was reduced to 0.25 parts in KSD due to smaller SA to volume ratio of tablet. In-vitro dissolution testing of SD with and without compritol was conducted in purified water using USP dissolution apparatus I. The hydrophocity imparted by compritol allowed complete drug release in controlled manner by preventing re-crystallization of drug within the tablet. But, the trend was reversed leading to incomplete drug release when the total weight of tablet increased gradually from 100 to 600 mg. Thus, it was confirmed that glyceryl behenate was a promising lipid excipient to prepare solid dispersion based oral controlled release formulation [59].

A study was conducted to develop CR matrix formulation of Glipizide based on Spray dried dispersion using various grades of HPMC-AS and Plasdone S-630 as SD carriers. The SSD were manufactured using automated spray dryer under optimized process variables and the obtained SDD were compressed into tablet using compaction simulator. The drug was entrapped in amorphous form within homogenous system with about 60% drug loading efficiency and the same was confirmed through well established physico-chemical characterization evaluation parameters. Supersaturated micro-dissolution testing of different SDDs in FaSSIF revealed extended super saturation up to 3 h with approximately 5–14 folds solubility enhancement in comparison to the crystalline form of drug. Amongst the study of two SD carriers, HPMC-AS showed higher super saturation. Again, the M & H grades of HPMC-AS maintained that state effectively for prolonged time. The improved rate and extent of drug release was obtained from matrix tablet during the 24 h dissolution study with the achievement of controlled release following zero and slow first order release kinetics. It was confirmed that the combined effect of HPMC-AS as well as HPMC prevented the re-precipitation of drug in crystalline form the super saturated solution and helped to develop stable and controlled release formulation [60].

Park et al. designed pH-independent controlled release formulation consisting of nanosized solid dispersion that is adsorbed on hydrophilic silica known by brand name Aeroperl® 23 24 300/30 to modify solubility and release rate of Valsartan. FT-IR (Fourier Transform Infrared) study proved that Ternary SD system formed had intermolecular hydrogen bonding and changed crystalline drug into an amorphous state. The dissolution study in 0.1 N HCL with acidic pH of 1.2 showed that the in-vitro release rate of drug from SD system prepared using carrier poloxamer 407 was drastically increased when compared to pure drug or commercially available Diovan® tablet. The dissolution enhancement was obtained due to nanosizing of SD system from 600 to 150 nm within the first 2 h of dissolution process. The CR tablets loaded with VAL SD and consisting of HPMC 4000 confirmed pH-independent zero-order drug release kinetics along with the desired stability profile during accelerated stability testing for six months with least inter-subject variability in Cmax in healthy human volunteers when compared to the outcomes of commercial product Diovan® 37 [61].

Xu et al. studied ER dosage forms consisting of drugs which are potent and aqueous insoluble in nature comprising of novel combination of lipid excipient as SD carrier along with a matrix of hydrogel polymer. Tacrolimus SD was prepared with glyceryl behenate and Pluronic F127 as the SD carriers using hot melt method. Afterwards the SD was embedded within hydrogel matrix consisting of HPMC and lactose. The powder mixture obtained was directly compressed into tablets. The dissolution study revealed that the in-vitro release rate of drug was considerably enhanced due to the lipid solid dispersion carrier, and the addition of hydrophilic polymer HPMC contributed to the development of stable formulation. ER tablets consisting of Tacrolimus SD revealed that the drug release rate was controlled up to 24 h and the release profile fitted to the K-Peppas model with n value of 0.85 indicating that the rate controlling mechanisms are diffusion and erosion based. The release profile of the formulation could be manipulated based on the composition of hydrogel matrix, especially the type and the proportion of HPMCs. The SD was melted and combined with hydro-gel polymer HPMC in a single step using Hot melt technique to obtain uniform distribution of the melted SD within the tablet hydro-gel matrix and achieve desired release profile [62].

Sustained release (SR) oral tablets based on the solid dispersion of poorly water-soluble drug Disulfiram (DSF) was developed and characterized by Shergill et al. The main purpose of the formulation was to increase aqueous solubility to improve the bioavailability along with the reduction of the metabolism and degradation of orally administered drugs due to the low pH and enzymatic activity of the stomach. SD were prepared from two different polymers namely Kolliphor P188 and P237 using hot melt method with DSF loading of 43 and 46% respectively in amorphous form. The tablets were manufactured from two different sustained release polymers namely Kollidon SR and Hypromellose to obtain sustained release of drug sand protect it from degradation in acidic environment of stomach. The addition of Kollidon SR in 80% ratio to the SR tablet prevents the degradation of drug in gastric pH for about 1 h and 10 min. Kollidon SR resulted in only 16% degradation after 2 h compared to HPMC in same ratio that lead to 75% degradation after 2 h. The release profile of drug from the formulation depends on the percentage loading and the sustained release polymer used. Thus it was conclude that HPMC provided much rapid drug release rate compared to another polymer Kollidon [63].

Nguyen et al. designed a sustained release SD of Isradipine using swellable polymers PEG 6000 & HPMC 4000 by melting method to enhance drug dissolution rate along with sustaining the release rate of drug from the formulation. HPMC 4000 was used for the swelling capability along with the common SD carrier PEG 6000 to provide an environment suitable for the swelling of HPMC 4000 which improved the drug dissolution by converting the crystalline form of API into an amorphous form by forming molecular interaction. In this research, the most crucial problem of SR dosage forms was addressed which is dealing with poorly water-soluble drugs that lead to low bioavailability. The addition of such low aqueous soluble drugs into SR SD carriers could overcome the above mentioned problems by improving the solubility and dissolution rate of insoluble drug leading to enhanced oral absorption along with obtaining sustained drug release using suitable SD carrier [64].

The less published fact of the synergistic effect of dissolution enhancement and controlled drug release was focused by Tran et al. using model drug Isradipine (IS). Solid dispersion containing the model drug was prepared by the melting method using PEG 6000 as the SD carrier. The prepared SD was added into polymer PEO N-60 K to obtain the controlled release of drug. The physical mixture and SD were exposed to physico-chemical characterization by PXRD (Powder X-Ray Diffraction) and FTIR respectively to study the physical form of drug in SD and interactions between drug and SD carrier. The designed formulation was successful in increasing and controlling the dissolution rate of drug simultaneously throughout the GIT in both gastric and intestinal environment. Such an approach would be helpful to researchers to obtain the desired steady state blood levels of drugs with minimum peaks and troughs for prolonged time duration after a unit dose incorporation [65].

Moneghini et al. studied microwave irradiation (MW) technique to prepare solvent free SR SD utilizing Ibuprofen (IBU) as a model drug and glyceryl monostearate (Imwitor 900, GM) as a lipophilic SD carrier in varying ratios. The physical characteristics of SD performed by different evaluation parameters like DSC (Differential Scanning Calorimetry), PXRD and hot-stage microscopy (HSM) demonstrated a significant correlation of the solid state of IBU before and after treatment with MW technique. The in vitro drug release of the irradiated solid dispersion samples was evaluated through the dissolution rate studies and it revealed that the GMS was capable to achieve sustained drug release profile based on matrix erosion. Hence it was confirmed that the microwave irradiation is a novel and interesting technique to prepare drug-carrier systems [66].

SR microspheres of Nitrendipine comprising of SD were manufactured in single step process with the purpose of improving bioavailability of poorly soluble drug and achieving extended time to reach C_max value. Solid dispersion carrier HPMCP (Hydroxy Propyl Methyl Cellulose Pthalate) and sustained-release polymers Eudragit RS PO and ethylcellulose were utilized together to manufacture the microspheres using spherical crystallization technique also referred as quasi-emulsion solvent diffusion method. The prepared microspheres were evaluated based the micromeritics and the release rate study. It was interpreted that the particle size of microspheres was greatly influenced by the rotation speed. During the dissolution study, it was observed that the drug release from microspheres was prominently affected by the quantity of dispersing agents or retarding agents added in the microspheres. The desired controlled release of drug from microspheres can be obtained by selecting suitable combination ratio of dispersing agents to retarding agents. Additionally, the in-vivo absorption study of Nitrendipine microspheres was performed in 6 healthy dogs. The physicochemical characterization done by PXRD and DSC (Differential Scanning Calorimetry) confirmed the conversion of crystalline structure of drug into amorphous form due to SD formulation. The accelerated stability study performed for three months at 40 ͦ C and RH of 75% showed no significant change in drug release rate and drug content of the microspheres. The bioavailability of the SR microspheres was compared with marketed formulation (Baypress tablets) and conventional formulation and the F_r values obtained were 107.78% and 309.82% respectively [67].

A study was conducted to prepare microcrystalline dispersion (SMD) films of olanzapine (OLZ) to improve the dissolution rate. The effect of different hydrophilic polymers was checked in SMD film namely PVP, poloxamer 188, poloxamer 407 and Soluplus. The manufactured films were exposed to particle size and shape analysis, hydrogen bonding interactions study, thermal study and in vitro drug release rate in simulated intestinal fluid. Particle size of OLZ in all SMD films was obtained in the range of 42 to 58 µm. The maintenance of crystalline state of OLZ throughout the formulation process was confirmed based on Attenuated Total Reflectance Fourier Transform Infrared spectroscopy, DSC and Hot-Stage Microscopy (HSM). In vitro drug release rate of formulations showed better IR profile in comparison to the drug alone. The best IR drug release profile was obtained in SMD films with Poloxamer 188 mostly due to its higher hydrophilicity and surfactant properties in comparison to the other water soluble polymers checked. Hence, it was concluded that proposed formulation was effective in achieving enhanced oral bioavailability based on in-vitro and in-vivo evaluation conducted [68].

A study was conducted to prepare solid dispersions of a low aqueous soluble drug Nifedipine. SDs was manufactured using Methocel and coated upon sugar spheres using fluidized-bed coater. First of all, a common solvent system consisting of mixture of acetone:water in 7:3 ratio for the spraying of nifedipine and HPMC together was finalized based on optimization. The nifedipine SDs containing HPMC in Nifedipine:HPMC ratio of 1:1 and 1:3 showed broad peak in comparison to the peak demonstrating the MP of pure nifedipine upon characterization with DSC. The in-vitro release study of formulation revealed that release rate of nifedipine fastened as the ratio of SD carrier HPMC was increased. The incorporation of surfactant Tween 80 in dissolution medium while conducting the dissolution study enhanced the release rate of drug. It was observed that the higher proportion of HPMC in SD formulation reduced the solubilization effect of Tween 80 [69].

Patil et al. conducted a study to develop solid dispersion of metformin hydrochloride using HPMC K100M as the SD carrier using solvent evaporation and co-grinding method. The effect of drug: carrier ratio on the release rate of metformin hydrochloride was understood by the dissolution study. The characterization of dispersion was conducted using FTIR, UV, DSC and PXRD study. The formulation was subjected to optimization and the batch finalized was kept for accelerated stability testing based on ICH guidelines. The Release data were fit into pharmacokinetic release equations to interpret the drug release pattern. Considering all the characterizations, SD with 1:4 and 1:5 drug: polymer ratio were selected as the most promising formula for prolonged-release oral dosage form of metformin [70].

Sahoo et al. developed Sustained release formulation of Verapamil HCl incorporating solid dispersion to obtain twice a day administration. The release of drug from tablets was controlled by using SR polymer Eudragit RLPO or Kollidon in varying ratios of drug: polymer. The physical mixtures and solid dispersions were prepared in ratios of 1:1, 1:2, and 1:3 of Verapamil HCl: Eudragit RLPO / Kollidon® SR by simple mixing and solvent evaporation methods respectively. The physico-chemical characteristics of solid dispersion and absence of interaction between drug and carrier were confirmed based on graphs of FTIR, X-ray diffraction, and differential scanning calorimetry. The sustained release formulation was designed as tablet consisting of solid dispersions or physical mixtures of Eudragit RLPO/ Kollidon® SR. The in vitro release rate of drug from tablet was checked for time duration of 12 h in simulated Intestinal fluid using USP dissolution apparatus type II- Rotating Paddle. The in-vitro study showed that Eudragit helped to extend the release rate profile of drug to achieve twice a day administration whereas Kollidon® SR prolonged the release rate to achieve thrice a day administration. Based on the drug release data and the release kinetic equations, it was confirmed that SR tablet containing solid dispersions of Eudragit RLPO was more suitable to control the release of verapamil [71].

Tahseen et al. formulated sustained release tablet of Carvedilol using solid dispersion technology to increase the solubility of Carvedilol using Poloxamer 407 and PVP K30 as SD carriers. The sustained release profile of drug from the forulation was obtained with the help of release retarding polymer HPMC K15 in appropriate concentration. The tablets were directly compressed and analyzed for physicochemical properties. The dissolution study was carried out in pH 1.2 for initial 2 h followed by 12 h release study in simulated intestinal fluid using USP Type II Rotating paddle apparatus. The inverse relationship was observed between HPMC concentration and Carvedilol release. The batches F1 and F4 made with 20 mg of HPMC K15 showed 97% drug release up to 12 h whereas batches F2, F3, F5 and F6 containing 40 mg and 60 mg of HPMC K15 showed 98% drug release upto 14 h. Batches F1 and F4 containing SD of Poloxamer 407 and PVP K30 showed early t_50% of 6.4 h compared to 9.5 h of tablet formulation F7 containing only drug. Hence it was confirmed that SD technique is a successful and capable method for achieving sustained release for the low aqueous soluble drugs [72].

Halder et al. conducted a study with an aim to prepare sustained release solid dispersion (SRSD) of Carvedilol with 25% w/w drug loading to enhance dissolution. The study even explored the applicability of different drying techniques available for industrial access. SRSD of Carvedilol was designed using different ratios of polymers Kolliphor® P188 and Eudragit® RSPO and their physicochemical characterization was undertaken. The increase in dissolution rate was confirmed based on the dissolution study in sink and supersaturated conditions. On the basis of solubility study, the batch consisting of Kolliphor® P188 and Eudragit® RSPO in 50:25% w/w ratio showed the highest solubility and was proposed as optimized composition to prepare SRSD-CAR to undertake further characterization. The physical characterization based on the crystallinity study confirmed the amorphous form of CAR with higher solubility. The compatibility study between CAR and SD carriers based on FTIR showed no significant deviation verifying the absence of significant interactions. Also, the SRSD-CAR revealed immediate formation of nano-particles upon dispersion in water. The in vitro drug release study showed dissolution rate enhancement with controlled release of CAR compared to the crystalline form of CAR. The release rate data of Carvedilol were fitted into different release kinetics equations with the Korsmeyer Peppas equation giving the best correlation. Thus the main release controlling mechanism is diffusion. There was no significant effect of method of preparation of SRSD-CAR formulations i.e. rotary vacuum drying or freeze drying on the drug release rate and mechanism. Hence, it can be concluded that the selected Sustained release SD approach is suitable for designing the formulation of CAR with improved biopharmaceutical characteristics [73].

Jujube et al. investigated the characteristics of controlled release solid dispersions (CR-SDs) consisting of drug Aceclofenac, release controlling polymer polyethylene oxide, solid dispersion carriers namely Gelucire 44/14 & poloxamer 407 and pH modifying agent sodium carbonate. The immediate release and controlled release solid dispersions were designed and it was summarized that IR SDs containing the sodium bicarbonate significantly improved the dissolution rate of aceclofenac, whereas the CR SDs containing PEO sufficiently maintained constant drug release rate. CR SDs had large droplet size and higher surface charge in comparison to immediate release solid dispersions. The pH modifying agent acts as release rate modifier by changing the crystalline behavior and hydrogen-bonding interaction of drug and by controlling the micro environmental pH. Near-infrared images were captured that demonstrated a modulation of the PEO concentration to maintain the pH modifier inside the system to obtain the constant release rate of Aceclofenac. Finally, it was summarized that the dissolution rate of solid dispersions of water insoluble drug Aceclofenac consisting of PEO is significantly affected by micro-environmental pH, particle size and charge, pH modifying agent and the concentration of PEO [44].

Uegaki et al. not only developed controlled-release solid dispersion granules but also explained the release mechanism behind the controlled release of low aqueous soluble drug Nifedipine. To procure the objective, the SR granules were prepared using Hydrated Silicon Dioxide (HSD) and PVP by wet granulation method. Then, the solubility enhancement effect of PVP as SD carrier on Nifedipine was estimated. To optimize the rapidly dissolving granule of NIF, firstly suitable binder was selected and then the effect different ratios of drug and binder were studied. Immediate release granules of Nifedipine (NIF) containing binder erythritol and lubricant HSD were formulated. DSC study confirmed the reduced crystallinity of NIF in the granules. The composition of immediate release granules was cross checked by conducting experiments with other 6 poorly water-soluble drugs to confirm the output. It was confirmed that the optimized composition lead to dissolution enhancement of all drugs from the granule just as observed in NIF formulation. These studies prove that use of HSD in solid dispersion granules help to obtain rapid dissolution rate of the drugs with low aqueous solubility. Afterwards PVP’s effect on the drug dissolution rate from the immediate-release granules was investigated. The sustained release effect of polymer PVP on the IR SD granules consisting of these 7 drugs was recorded as no effect (rapid dissolution), middle effect or strong effect (sustained release). To understand the SR mechanism of drug from the SD granules, FTIR was undertaken to check the intermolecular interactions between the drug and HSD or PVP. Finally it was interpreted that the appropriate balance between the these interactions is essential to achieve the extended release of the drug [74].

Cai et al. worked on traditional Chinese medicine named Borneol that is helpful in enhancing in-vivo bioavailability and availability to the brain. The drawback of Borneol is gastric irritation in high doses. To check the applicability of Borneol, the model drug taken was gastrodin which is the principal biologically active constituent of the Chinese drug “Tianma” (Rhizoma Gastrodiae). SR SDs co-loaded with both were formulated using EC and HPMC as SR polymers. The solid dispersions were characterized based on SEM, Differential Scanning Calorimetry and powder X-ray diffractometry to check the entrapment of API within the SR SD. The analysis confirmed that both medicines were entrapped in an amorphous state within SD carrier. The dissolution study of both drugs concluded that the in vitro release pattern follows Higuchi model. Afterwards, the SDs were analyzed for gastric irritation and the brain targeting and it was interpreted that the capacity of SR SDs to cross BBB was slightly weaker with brain targeting index of 1.83 compared to 2.09, but the gastric mucosa irritation was significantlty reduced. Thus it was summarized the SR technology is effective to overcome stomach irritation caused by borneol in addition to maintaining appropriate transportation ability for oral brain-targeting drug delivery [75].

Lu et al. developed a SR formulation consisting of SD of drug Ivermectin within a lipid matrix polymer hydrogenated castor oil using Solvent-melting technology aimed for subcutaneous route. The physical characterization of SD was done by SEM, PXRD and FTIR, whereas the in-vitro release rate of drug from SR SDs was pocessed with HPLC. The Pharmacokinetic parameters of drug and its effectiveness against the ear mange mite were determined using rabbit as animal model after a unit s.c incorporation of SD formulation. It was observed that the Ivermectin was able to trap amorphously in a lipid matrix in ratio lower than 1:3 for IVM: HCO. The drug excipient interaction was absent except for hydrogen bond within the amorphous SDs. The amorphous SDs showed extended drug release from formulation when compared to physical mixtures of drug and HCO. The drug release rate was found to reduce when the drug: carrier ratio was lowered. The release rate mechanism was diffusion controlled. The Cytotoxic study revealed that SD showed low toxicity to MDCK cells compared to pure IVM. The plasma concentration of IVM in SD with 1:3 ratios was maintained more than 1 ng/ml for forty nine days. Increased values of pharmacokinetic parameters AUC, Mean Residence Time and T_max were observed for SD of 1:3 compared to IVM group. The solid dispersion enhanced bioavailability of IVM by 1.1-folds in comparison to drug alone in rabbits along with longer persistence against rabbit’s ear mites than commercial IV formulation. Hence, the study proved that solid lipid dispersion technique is effective for the development of subcutaneous IVM formulations [76].

A work was conducted to develop SR SD of Metoclopramide HCl using solvent evaporation method. Different synthetic SR excipients like Eudragit RSPO & Eudragit RLPO as well as natural polymers like guargum & Egg albumin were used in combination to prepare SR SD. The SD were characterized by different evaluation properties like solubility, partition coefficient, % drug content, cumulative drug release and flow property characteristics. All of these parameters were found to be in acceptable range. The SDs was exposed to X-Ray Diffraction and SEM and it was interpreted that the drug was dispersed amorphously into a solid dispersion carrier. The SR SD was also evaluated for pharmacokinetic parameters by in-vivo studies on Albino Wistar rats. The in-vitro release study of SD proved that the sustained release of Metoclopramide HCl for at least 12 h was obtained along with the increase of bioavailability leading to reduction in dosing interval and dosing amount. Eventually the formulation reduced plasma level fluctuations minimizing dose related side effects. Apart from that, the formulation was cost effective and improved the patient compliance and drug efficiency [77].

Fan et al. conducted a study to design SR SD of curcumin in one step process by hot melt extrusion technology. The formulation was evaluated based on several in vitro as well as in vivo parameters to serve the objective. Firstly the crucial parameters related to process like temperature, speed of screw and rate of cooling were optimized. The Physicochemical characterization of SR SD was carried out based on DSC, PXRD and FTIR. It was concluded that SR pH independent polymers Eudragit RS & Eudragit RL used to sustain the release have good dispersibility with drug. The DSC study proved that the physical form of dispersed Curcumin within the SD was amorphous form. The Stability study performed for 6 months showed no difference in the physical characteristics of curcumin. The study using release kinetics models confirmed that the drug release mechanism from the SR SD was combined diffusion and dissolution based. The in-vivo study proved that the bioavailability of the Curcumin in SR SD enhanced to 223.44% compared to curcumin alone. Hence it was justified that HME is a successful technique to prepare SR SD of Curcumin or any other poorly water soluble drug, which not only improve bioavailability of drug but also stabilize effective plasma concentration [78].

Osmotically controlled release drug delivery systems

Battu et al. developed multiparticulate based pulsatile drug delivery system of Nifedipine for the cure of angina pectoris based on chronotherapy to enhance the aqueous solubility which limits its bioavailability. SD of drug was processed by kneading technique using sodium starch glycolate and guar gum in two ratios of 1:1 and 1:2. The SD were coated on non-pareil sugar spheres of about 450 µm size by Solution layering method to obtain IR and CR pellets. CR pellets were applied with second layer of Eudragit L 100 and Eudragit RS 100 to obtain pulsatile pellets. The pellets were analyzed based on saturation solubility data, Fourier Transform Infrared spectroscopy, Differential Scanning Calorimetry, micromeritic properties, microscopy, assay, in-vitro drug release rate, in-vivo study and accelerated stability studies. SD enhanced the solubility of drug by 130-folds due to intermolecular binding of drug and carriers. FTIR spectra and DSC thermo grams showed absence of prominent interactions between drug and SD carriers. Fluidization technique helped in producing spherical pellets with desired characteristics. The solution layering method used lead to high drug content above 80% with maximum drug release at the end of 12 h along with lag time of 6 h. The increase in solubility of drug with solid dispersions improved pharmacokinetics and bioavailability. The physico-chemical characteristics of pulsatile formulations were maintained during stability study. Thus, it was demonstrated that the multi-particulate systems of Nifedipine are applicable in chronotherapeutic treatment of the diseases based on circadian rhythm [79].

Cheng et al. performed a study wherein Osmotic drug delivery system was designed consisting of a bi-layer tablet of Flurbiprofen (FP) solid dispersions (SDs) to enhance the solubility of the low aqueous soluble drug and simultaneously control the drug release to achieve zero order constant release rate. The formulation was optimized based on central composite design-response surface methodology (CCD-RSM). The SD containing drug and carrier PVPVA64 was prepared using hot melt extrusion method, wherein FP was entrapped in amorphous state within the carrier which was concluded on the basis of thermodynamic properties study of FP, PVPVA64 and the solubility study of drug. FTIR confirmed the intermolecular hydrogen bond probably formed between FP and PVP VA64 in FP-SD. The drug release from the osmotic tablet followed constant release kinetics based on the mathematical model of zero order and it showed good predictability with regression correlation approximately 1 between theoretical and observed values. Based on the data, it was confirmed that Osmotic pump of FP SD was efficient enough to serve dual purpose of solubility enhancement and predetermined zero order controlled release rate of drug [80].

Yang and team designed a novel formulation based on osmotic drug delivery system in the form of capsule to achieve controlled release. The osmotic pump capsule consisted of gliclazide (GLC) solid dispersion. The capsule shell was prepared as semi-permeable membrane of cellulose acetate using wet phase inversion method. The pores were generated in the capsule shell membrane using polymers Glycerol and kolliphor P188. The shells were not only filled with GLC solid dispersion but also pH modifiers. Unlike IR formulations, sodium carbonate was selected for dual purpose of osmogent and effervescence generating adjuvant to obtain constant release rate of Gliclazide. The ternary SD of drug was prepared using SD carriers PEG 6000 and kolliphor P188 using solvent evaporation technique, obtaining solubility increase of around 2.1 folds compared to GLC alone. The in-vitro dissolution study of the capsule was conducted and the drug release rate was correlated with the components of the coating and presence of pH modifying agent. The drug release data of the optimized formulation fitted with zero-order release model with CDR of 91.32%. The bioavailability study of the capsule formulation showed a relative bioavailability of 102.66 ± 10.95% in comparison to the commercial tablet, suggesting that both formulations are bioequivalent. Hence, it was proved that it is possible to combine solid dispersion and AMC system to obtain novel controlled delivery system as a preferable alternative for controlled release the water-insoluble drugs [81].

Li et al. developed a novel capsule based CR formulation of low aqueous soluble and ionizable drug Flurbiprofen. The target was to improve oral bioavailabilty through solubility enhancement by preparing pH-modulated SD of drug. The formulation was also aimed to reduce the plasma concentration fluctuation and dosing frequency. The SD containing drug, low molecular grade Kollidon and sodium carbonate in a weight ratio of 1:4.5:0.02 was manufactured by solvent evaporation technique. Perfusion method was used to prepare the semi-permeable capsule shell consisting of film forming agent cellulose acetate. The shell was filled with the tablets prepared from the mixture of SD, permeation enhancer and viscosity enhancer. The formulation was optimized based on RSM using experimental design Box-Wilson Central composite design to understand the effect of significant variables on the outcomes. The in vitro drug release study was performed and the corresponding regression coefficient of drug release data and CDR after 12 h was exposed to mathematical release models. The actual response values and predicted values showed good resemblance with each other. The optimized formulation showed constant release of drug following zero order. The pharmacokinetic study was conducted with Beagle dogs. The bioavailability study indicated the relative bioavailability of 133.99% of the novel SD formulation compared to the marketed formulation. Thus the strategy studied by researchers proved to be significant in achieving the desired goals [82].

Banerjee et al. provided a unique way to deliver poorly water-soluble, narrow therapeutic index drugs at a constant rate for the effective cure of life-long diseases like diabetes mellitus and cardiovascular diseases by improving dissolution rate and bioavailability of such drug. The technique was based on osmotic DDS, wherein combined approach of controlled porosity and solubilization was preferred. He developed SD of pH dependent low aqueous soluble drug gliclazide GLZ using HPC as a SD carrier by hot melt extrusion method. Then, CPOP of SD was formulated to release GLZ up to 16 h in a controlled manner. The formulation optimization was conducted undertaking the type and composition of pore forming agent and % weight gain of coating solution as significant independent variables. The final optimized formulation revealed that the major regulating factor behind the zero order constant release of drug was the osmotic pressure of the dissolution medium rather than the pH of the medium and the rotation speed used. The pharmacokinetic study performed based on convolution concept proved that the proposed osmotic pump was better in preventing plasma fluctuations and in controlling blood glucose level in comparison to the conventionally available sustained release formulations of GLZ [5].

Delayed release drug delivery systems

Riekes et al. prepared FDC of ezetimibe and lovastatin drugs as Enteric coated formulation with the aim of preventing the degradation of drug into its hydroxyacid derivative in the acdic medium. The formulation was enteric coated using fluid bed coating. The manufacturing process included two-steps in which firstly the glass solution of two drugs and SD carrier Soluplus® was coated on sucrose beads and then further it was top-coated with pH dependant polymers of Eudragit L100 and Eudragit L100-55. The formulation analyzed based on PXRD, SEM (Scanning Electron Microscopy), diffraction & dissolution studies in both gastric and intestinal pH interpreted the effect of bead size, enteric polymers and coating time. The study on bead size concluded that reduced bead size may tend to agglomeration of beads leading to drug release at low pH, especially because of uneven top coating. Both the grades of enteric polymers used prevented major proportion of drug to release in stomach and allowed immediate release in the intestinal pH. The optimized coating time for perfect thickness was obtained 0.25 and 0.5 h respectively above pH 5.5 and above pH 6. The drugs were entrapped in molecular form within SD using carrier Soluplus® and it was concluded that Eudragit L100 formulations provide more proportion of drug release in stomach due to concave pores on the surface. The formulations were exposed to accelerated Stability studies of half year and the results showed no change in physicochemical properties and in-vitro release data of both drugs when compared to initial data [83].

Zhao et al. designed enteric solid dispersion (SD) of Nimodipine to ovecome the limitations of low bioavailability and reduced clinical efficacy of the conventional solid dosage forms of NMD. Nimodipine (NMD) belong to the category of dihydropyridine calcium channel blocker which act selectively on cerebral blood vessels. It is prescribed to prevent and treat cerebro-vascular disorders, especially delayed ischemic neurological disorders which are associated with circardian rhythm. The solid dispersions of NMD were prepared by Co-evaporation and melting method using HPMCAS and HPMCP. The delayed release tablet consisting of SD was prepared using Kollidon SR, Eudragit RS PO and PEO, N-12 K. The prepared SDs were characterized by DSC and PXRD to interpret the physical state of the dispersed NMD within the polymer matrix. The dissolution study of NMD-SD showed significantly enhanced dissolution of about 80% when compared to pure drug and physical mixture. A DR tablet was prepared by directly compressing the SD of NMD. The dissolution study of DR formulation containing NMD-SD showed nominal drug release (LT 10%) in 0.1 N HCl in the initial 2 h study and showed the drug release of around 32.1%, 75% and higher than 90% at pH 6.8 at the time points of 4, 10 and 14 h respectively. So, it was concluded that the proposed formulation was feasible for industrial applicability [84].

Overhoff et al. designed enteric powder consisting of solid dispersions of Itraconazole using HPMCP and Eudragit L100-55 by Rapid Freezing method. The influence of different composition characteristics that affect the release of drug from enteric SD under sink and non-sink conditions like polymer type, drug:polymer ratio, and particle structure were evaluated. The miscibility of drug with each of the polymer was evaluated by Modulated DSC. The curves showed that 60% ITZ was completely miscible for both polymers and 70% was miscible in HP-55. Glass transition temperatures of high potency composition correlated with predicted Tg’s based on Gordon–Taylor equation, and the pure amorphous regions in the exotherms revealed the phase separation during particle formation. The differentiation between completely miscible i.e. low potency and partially miscible i.e. high potency compositions was checked based on different evaluation tests namely dissolution study, PXRD, SEM and surface area analysis. The Dissolution studies of completely miscible ITZ compositions revealed that the miscibility is playing a significant effect on drug release, especially under sink conditions, and the drug release through the pH dependant polymer follows square root diffusion. The dissolution study in supersaturated conditions revealed that the partially miscible components had highest saturation equilibrium solubility between 10.6—8 times compared to 15—19.6 times observed in low potency compositions and they also exhibited higher cumulative extents of super saturation. However, these completely miscible compositions precipitated rapidly which drastically lowered AUCs with p < 0.05. So it was concluded that the parameter significantly affecting drug release in sink condition is the miscibility of the solid dispersion, whereas the one affecting supersaturated dissolution profiles is potency [85].

Controlled release solid dispersion granules of weakly basic drug Verapamil HCl were manufactured by solvent evaporation method to ensure that drug release occur unhampered at higher pH values. Different Sustained release polymers like ethyl cellulose, HPC and pH dependent polymers like Eudragit L and Eudragit S were utilized to prepare solid dispersion granules to obtain constant release rate of the drug, and to prevent the reduction of drug release rate at the basic pH. CR formulation was designed by adding Eudragit L in EC network which may help to prevent the undetermined drug release at acidic pH and increase release of weakly basic drug at basic pH. The enteric polymers used in SD namely Eudragit L and Eudragit S showed different behaviour in terms of solubilization effect and the release of active substance. The drug release data were fitted to Higuchi and first-order kinetic models and calculated correlation coefficients were almost same for both equations making it difficult to differentiate between the mechanisms. As a result, the mathematical models were implemented and it was confirmed that the release controlling mechanism in SD was diffusion, except for batches with greater proportion of enteric polymer. The SD was exposed to 2 years stability studies based on real time, and the results confirmed no change in the amorphous nature, IR spectra and Differential Thermal Analysis of formulation. Even the dissolution study of the formulations showed almost same drug release profiles after 24 months of the stability studies, eventually proving that the designed formulation was stable with dispersed drug in amorphous form [86].

Site-specific drug delivery systems

Vo et al. prepared a gastro-retentive drug delivery system that would serve dual purposes of high residence in gastric environment through several approaches and potential induction of in situ supersaturation overcoming poor and unstable bioavailability of drugs with low solubility. The aim was achieved by preparing floating pellets with bioadhesive nature, within which SD containing amorphous drug is loaded in a one step process using HME. The model drug selected was Felodipine with matrix-forming polymers used Hydroxypropyl cellulose (Klucel™ MF) and hypromellose (Benecel™ K15M). The foam pellets used sodium bicarbonate to obtain the expansion of CO₂ during the melt-extrusion process. The effect of proportion of formulation components upon the nature of pellet was understood based on 2ⁿ full factorial experimental design. The HME process successfully trapped the drug in an amorphous form within the polymeric matrix. All the foam pellets had high porosity and showed immediate floating in simulated gastric fluid without any lag time, and the pellets remained floating for about half day. The pellet-specific floating force obtained was 4800 μN/g which became greater prominently during initial hour, and it remained comparatively constant for about nine hrs. The most important factor affecting floating force was the proportion of sodium bicarbonate in the pellets. The ex vivo bioadhesion study was performed using porcine stomach mucosa and the bio-adhesive force of the pellets obtained was around 5 mN/pellet, which was minimum 5 times greater compared to the gravitational force obtained by the pellets saturated with water. The drug release study was performed in 0.1 N HCl and the sink condition was maintained using 0.5% sodium lauryl sulphate. The dissolution study of all 11 formulations showed controlled release upto 12 h with the percentage release of 5–12%, 25–45%, 55–80%, and ≥ 75% at time points of 1, 3, 5 and 8 h respectively. A supersaturated drug solution was formed in simulated dissolution medium, and almost 10-folds higher concentration was obtained and maintained compared to pure felodipine. The amount of Drug loaded in SD and HPMC proportion significantly affected dissolution after 3 h [87].

The study was performed to design gastroretentive floating tablet consisting of SD of low aqueous soluble and permeable drug to improve the solubility along with the retaining the drug in gastric medium for achieving better absorption profile. The drug studied was antibiotic named Cefpodoxime proxetil belonging to third generation cephalosporin category. The oral bioavailability of drug is only 50% and half-life of drug is in range of about 2.09—2.84 h. The carriers selected to prepare SD were PEG 4000 and PEG 6000. The optimization was performed using face centred cube design (FCCD) and the optimized batch found out was SD8. It was observed that the highest solubility of 18.93 mg/ml and the drug release rate of 94.66% in gastric medium were obtained from the optimized batch in comparison to physical mixtures and pure drug. It was proved that increase in the concentration of carrier leads to solubility enhancement and the increase in drug release of SD following first order kinetics. The optimized batch SD8 was incorporated in gastro retentive floating tablet based on effervescent approach containing HPMC of grade K15 M as the water swellable polymer and sodium bicarbonate as effervescent agent. The tablets were prepared by directly compressing the mixture and evaluated for various quality control parameters like thickness, hardness, friability, assay, weight variation, in vitro floating lag time & total floating time, % swelling index and dissolution study [88].

A study was conducted for the development of wax based floating pellets consisting of Sustained release Solid dispersion of drug protocatechuic acid. It is weakly acidic drug of hydrophilic nature. The low density approach was preferred to achieve extended gastric retention of drug along with the improvement in bioavailability. The matrix pellets were prepared with mixture of octadenol and MCC using extrusion-spheronization method coated with drug & ethyl cellulose solid dispersion using one step fluidized bed coating technique. The optimized pellets formulation showed sustained release for desired period of 12 h along with sufficient floating capability in gastric medium without any floating lag time. The drug release was based on non-fickian transport mechanism. The optimized pellets showed spherical structure with compact core during the structural analysis based on SEM. The FTIR, DSC and PXRD studies interpreted that the drug was dispersed in amorphous molecular form in the core of pellets without any significant interaction with the polymeric carriers. The stability study of optimized formulation confirmed the integrity and stability of amorphous SD of drug in the pellets [89].

La Fountaine et al. hypothesized that the large molecules like peptides may be delivered through oral route in the form of mucoadhesive patches may lead to enhanced absorption rate. This approach may be helpful in case of small molecules with poor solubility. So, a mucoadhesive matrix polymer was utilized to entrap amorphous solid dispersion of drug Itraconazole. Thermokinetic mixing process known as KinetiSol Dispersing technique was utilized to develop conventional solid dispersions of drug and carrier Carbopol 71G. The physicochemical characteristics of bioadhesive SD were investigated by using PXRD, calorimetry and LC (Liquid Chromatography) to determine the optimized formula. The bioadhesive strength of the dispersions was investigated with texture analyzer by attaching the SD to freshly cut intestinal membrane of pig. The optimized dispersion was used to prepare minitablets and coated with EC. The optimized formulation was evaluated based on in vitro and in vivo studies in rats. Thermokinetic mixing process resulted in 30% drug loading in amorphous form within dispersions successfully. Each SD formulation showed higher adhesive strength compared to its control without polymer during in vitro study. The prepared SD was compressed into minitablets and some minitablets were coated with EC. Both the types of minitablets were fed to rats through oral route. The minitablets showed extended release profile, and the in-vivo study in rats demonstrated higher bioavailability in case of uncoated minitablets in comparison to coated minitablets. Necropsy studies of enteric coated capsules containing minitablets also showed targeted release of drug at the distal part of intestine and good adhesion to the mucous membrane of GIT, but the overall performance was not evaluated due to limitations of rat model. Hence, all the findings obtained lead to conclusion that the further investigations in larger animals is required for the evaluated dosage forms due to favorable parameters like fluid volumes, pH, and transit times [90].

Mohac et al. proposed Multicomponent solid dispersions (MSD) as a drug delivery system that may lead to enhanced bioavailability through increase in solubility using model drug Irinotecan (IRN). The main objective was to significantly enhance intestinal permeation of the drug for protecting the drug in the gastric environment. The role of specific carriers like mannitol, inulin, poly (methyl methacrylate-co-methacrylic) acid and CAP were studied for that purpose. The drug-loaded spray dried microparticles of IRN were prepared and the comparative study with respect to pure IRN showed improved bioavailability based on in-vitro dissolution study and in-vivo permeation study through the colon. FTIR study showed no significant interaction between drug and excipients. The shape and size determination of microparticles was carried out by SEM images. The DTA confirmed that the nature of drug was not altered while the loading in the microparticles. The smaller particle size of microparticles as well as appropriate selection of excipients lead to increase in drug solubility as well improved permeation of drug through the intestinal membrane of colon. Hence, based on the in-vitro and in-vivo data it can be summarized that proposed MSD and the excipients are effective in enhancing the oral bioavailability [12].

Alhijjaj et al. investigated the stability of complex MSD of Felodipine for the clinical application. Felodipine Solid dispersions were manufactured by hot melt-injection moulding technique utilizing two types of mixtures containing Polyethylene glycol, Polyethylene oxide and surfactant namely Tween 80 or Vit E Tocopherol Polyethylene Glycol Succinate. The solid dispersions were formulated with different drug loading proportion and exposed to a different storage conditions. The formulations were characterized based on Microscopic study, DTA, spectroscopic evaluation and PXRD. The comparison of two blends showed that the semi-solid surfactant TPGS is superior to liquid surfactant Tween 80 in terms of solubilization effect on as well as it chemical stability to hydrophilic polymer leading to stable formulation. The systems with low drug loading showed better stability at storage conditions. On the contrary, the loading of drug over the saturation level led to the formation of crystals of metastable form of drug in the patches which ultimately reduced the stability of SD. The comparative analysis of the data sets was obtained based on normalization process and statistical calculation. The Felodipine patches with TPGS surfactant showed comparatively higher sensitivity to the aging process than the buccal patches containing Tween. The major factor causing instability in case of both surfactants is storage temperature rather than humidity. Hence a methodology was developed for exploring the complex stabilities of MSD [91].

Caro et al. developed a fast-dissolving film of Furosemide (FUR) of mucoadhesive nature to be administered by sublingual route. The objective was optimization of the bioavailability of drug by increasing the solubility that can guarantee enhanced and reproducible dissolution rate. FUR is a diuretic prescribed to reduce fluid retention in edema and to lower blood pressure, with variable bioavailability, due to abrupt gastrointestinal absorption because of various polymorphic forms that leads to low and pH-dependent solubility. The patch was made by the solvent casting technique entrapping FUR amorphously within SD which was confirmed based on DSC study. The solid dispersion form of FUR enhanced solubility compared to pure drug and it may lead to improvement in the bioavailability of drug along with providing good dissolution reproducibility. The films were evaluated for different physico-chemical parameters like assay, film thickness and weight variation. The drug-loaded film was considered suitable as elastomer on the basis of the results of Young’s Modulus, yield strength and the percentage elongation of break. The Mucoadhesive strength test was performed to identify the force needed to separate the film from mucosa and it was interpreted that the strength required was increased drastically upon increase in contact time up to 7667 N/m². The release rate of FUR from the film was rapid and well fitted to Weibull kinetic model. It was observed that the patch led to drug fluidity in higher mass through the sublingual mucosa into the systemic circulation. The film after application on the sublingual mucosa showed a massive drug flux in the systemic circulation. Hence, the work undertaken led to enhanced drug solubility and absorption of FUR providing faster therapeutic effect and predictable bioavailability for the effective treatment [92].

Karavas E et al. prepared pulsatile release formulations for the prevention of ischemic heart diseases. SD of Felodipine and PVP in 1:9 W/W ratios was prepared by solvent evaporation method. A compression coated bi-layered tablet was designed with the active core containing SD and coated with mixture of PVP and HPMC blends in various ratios. The drug release rate was modified based on the proportion of polymer in the coating layer. DSC studies of the different compositions proved their miscibility in all the blends ratios due to interactions amongst -OH and –CO groups. It was proved that the miscible blend improves the bioadhesive strength in comparison to pure HPMC which is desirable for the effect. The increase in bioadhesion was achieved because of higher wettability and flexibility of resulting from rapid dissolution of the PVP. During the dissolution study of bilayer formulation, firstly the disintegration of coating layer occurs followed by the IR of FELO from the SD core. The delayed release was attributed to combined mechanism of swelling and erosion of the polymers. The release time of FELO during a daytime is adjusted by changing the PVP/HPMC blend ratios, as represented by the mathematical equation t = 0.028 C^1.5, wherein C represents HPMC proportion in the polymeric mixture [93].

Solid dispersion based formulations of natural products

Herbal drugs offer a tempting substitution for synthetic drugs for the cure of vast range of diseases due to lower side effects. Natural products have potential therapeutic applicability but it cannot be used to the maximum extent due to the poor aqueous solubility of such drugs. Hence, Solid dispersion is a preferred technique to enhance the solubility limited dissolution and bioavailability of such candidates. Many herbal drugs had already been explored to SD technology to increase therapeutic efficacy and many still are potential candidates for same [94].

In the reported study by Hang et al., natural product silymarin with low aqueous solubility was loaded within solid dispersion along with hydrophilic carriers PVP and Tween 80 to develop a novel and stable formulation with enhanced dissolution rate, improved bioavailability as well as advanced hepatoprotective effect. The carrier PVP was attached onto the surface of crystalline silymarin maintaining the original crystalline characteristic of drug despite of converting the hydrophobic form of API to hydrophilic. After the preliminary screening amongst the different suitable hydrophilic carriers, PVP and Tween 80 were selected for SD and the proportion of carriers optimized was 5:2.5:2.5 with respect to silymarin: PVP: Tween 80. The optimized SD increased the solubility of drug by 650 folds along with maintaining the sufficient physical and chemical stability of silymarin in the solid dispersion for minimum half year. The silymarin loaded solid dispersion also demonstrated higher area under the curve and peak plasma concentration during in-vivo study in rats improving overall oral bioavailability of the drug by around 3 folds when compared to the marketed product at 95% confidence limit. The resultant silymarin product revealed advanced protection towards hepatic damage compared to drug alone or the commercially available product [95].

A study was conducted on the solubility enhancement of alkaloid Piperine extracted from black pepper showing enormous therapeutic applicability using solid dispersion technology. The SD of piperine was prepared using different hydrophilic carriers like sorbitol, PEG and PVP K-30 by solvent method to achieve superior in-vitro dissolution characteristics through enhanced solubility compared to pure drug and physical mixture. The increase in dissolution rate may be attributed to conversion of API into amorphous form, reduction in particle size as well as interfacial tension and increase in wetting property by using suitable hydrophilic carrier. The sugar based carrier sorbital provided added advantage related to hygroscopic nature. The selected polymers induced super saturation of drug and prevented re-crystallization of API in GIT and during storage up scaling the stability of drug. Hence, the current work eliminates the solubility limitation of Piperine to enable the potential therapeutic application in managing BP and lowering glucose & lipid level without opting for higher dose that may lead to toxic effects or costly formulation [96].

Hou et al. developed a novel oral formulation combining the solid dispersion technology with the nanotechnology for model drug curcumin using nanocarrier Rebaudioside A. Curcumin was selected due to its well known potential anti-inflammatory and anti-oxidant properties. RA is a natural sweetener and taste modifying agent along with many biological activities that makes it a carrier of choice in pharmaceuticals. RA have hydrophobic groups along with hydrophilic side chains rendering it the characteristic of forming ultra small sized micelles with size less than 4 nm in contact with aqueous solution. The hydrophobic drug curcumin was encapsulated within the self-nanomicellizing SD formed by RA to improve aqueous solubility, stability, in-vitro drug release rate, intestinal permeability as well as anti-oxidant property. The physicochemical characterization of SD was performed in solid and solution states. There was significant improvement in the aqueous solubility of curcumin entrapped in micelles compared to free version. The in-vivo pharmacokinetics study proved that there was enhancement in intestinal permeation and absorption of curcumin leading to about 19 folds hike in bioavailability. The studies conducted in rats confirmed the stronger anti-oxidant and anti-colitis activity of the nano micellar SD compared to unentrapped curcumin. Thus, it can be concluded that the formulation was successfully developed for the treatment of GIT disorders (Table 1) [5, 12, 44, 58–97].

Table 1.

Summary table of formulations based on Solid Dispersion

Drug	Type of Dosage form	Components of SD/ dosage form	Method of Preparation of SD	Reference
Gliclazide	Matrix compact	HPMC-AS H, M & L grades, Copovidone S-630	Spray-Drying technique	[58]
Itraconazole and Carbamazepine	CR tablet	PVP, Compritol 888	Holt melt extrusion, KinetiSol Dispersing	[59]
Glipizide	CR Matrix tablet	HPMC-AS, Plasdone S-630	Spray-Drying technique	[60]
Valsartan	CR tablet with nanosized SD	poloxamer 407, Aeroperl®, HPMC 4000	Hot melt method	[61]
Tacrolimus	ER Matrix tablet	Compritol® ATO888, Pluronic F127, hydrogel matrix of HPMC and lactose	Hot melt technique	[62]
Disulfiram	SR tablet	Kolliphor P188, Kolliphor P237, HPMC	Hot melt method	[63]
Isradipine	SR SD	HPMC 4000, PEG 6000,	Melting method	[64]
Isradipine	CR formulation	PEG 6000, PEO N-60 K	Melting method	[65]
Ibuprofen	SR SD	Imwitor 900 (GMS)	Microwave irradiation	[66]
Nitrendipine	SR microspheres	HPMCP, Eudragit RS PO, Ethyl cellulose	Quasi-emulsion solvent diffusion method	[67]
Olanzapine	solid microcrystalline dispersion (SMD) film	PVP, poloxamer 188, poloxamer 407, Soluplus® (SLP)	Hot melt Extrusion	[68]
Nifedipine	SD on pellets	HPMC, Tween 80	Fluidized-bed coating	[69]
Metformin hydrochloride	Prolonged-release oral dosage form	HPMC K100M	solvent evaporation and co-grinding method	[70]
Verapamil HCl	SR tablet	Eudragit RLPO, Kollidon® SR	Simple mixing and solvent evaporation methods	[71]
Carvedilol	SR tablet	Poloxamer 407, PVP K30, HPMC K15	Solvent Evaporation method	[72]
Carvedilol	SR SD	Kolliphor® P188, Eudragit® RSPO	Rotary vacuum drying or freeze drying	[73]
Aceclofenac	CR SD	Gelucire® 44/14, poloxamer 407, PEO, sodium carbonate	Melting method	[44]
Nifedipine	CR SD granules and tablet	Hydrated Silicon Dioxide, PVP	Solvent evaporation Method	[74]
Borneol & Gastrodin	SR SD	HPMC, EC	Solvent evaporation Method	[75]
Ivermectin	SR SD for subcutaneous route	hydrogenated castor oil,	Solvent melting technology	[76]
Metoclopramide HCl	SR SD	Eudragit RSPO, Eudragit RLPO, Guargum, Egg albumin	Solvent evaporation Method	[77]
Curcumin	SR SD	Eudragit RS, Eudragit RL	hot melt extrusion technology	[78]
Nifedipine	Pellets (Multiparticulate pulsatile system)	SSG, guar gum, Eudragi L100, Eudragit RS100	kneading technique	[79]
Flurbiprofen	Bi-layer osmotic pump tablet (OPT)	PVPVA64	hot melt extrusion technology	[80]
Gliclazide	CR osmotic pump capsule	PEG 6000, kolliphor P188, Glycerol, sodium carbonate	Solvent evaporation method	[81]
Flurbiprofen	CR SD Osmotic capsule	Kollidon 12 PF, sodium carbonate, cellulose acetate	Solvent evaporation method	[82]
Gliclazide	controlled porosity osmotic pump	hydroxypropyl cellulose (HPC-SSL)	hot melt extrusion technology	[5]
FDC of ezetimibe and lovastatin	Enteric coated beads formulation	Soluplus®, Eudragit L100® Eudragit L100-55®	Fluid bed coating	[83]
Nimodipine	Enteric SD tablet	HPMCAS, HPMCP, Kollidon SR, Eudragit RS PO PEO, N-12 K	Co-evaporation and Melting method	[84]
Itraconazole	Enteric SD Powder	HPMCP (HP55), Eudragit L100-55	Ultra Rapid Freezing	[85]
Verapamil HCl	CR SD Granules	EC, HPC, Eudragit L Eudragit S	Solvent evaporation technique	[86]
Felodipine	Bioadhesive Floating Foam Pellets	HPC (Klucel™ MF), HPMC (Benecel™ K15M), Sodium bicarbonate	Melt-extrusion process	[87]
Cefpodoxime proxetil	Floating tablet	PEG 4000, PEG 6000, HPMC K15 M	Solvent Evaporation method	[88]
Protocatechuic acid	Floating matrix pellets	octadenol, MCC, ethyl cellulose	Extrusion-spheronization method, fluidized bed coating	[89]
Itraconazole	Mucoadhesive SD minitablets	Carbopol 71G, EC	KinetiSol Technique	[90]
Irinotecan	Microparticles, Multicomponent solid dispersions (MSD)	PMMA, cellulose acetate phthalate	Spray-Drying technique	[12]
Felodipine	Multi-component hydrophilic SD Buccal patch	PEG, PEO, Tween 80 or Vit E TPGS	Hot melt-injection moulding method	[91]
Furosemide	Mucoadhesive sublingual fast-dissolving film	PVP-K90, Eudragit L100®, TEA	Solvent Evaporation method	[92]
Felodipine	Bilayered Pulsatile tablet	PVP, HPMC	Solvent Evaporation method	[93]
Silymarin	Silymarin loaded SD	PVP, Tween 80	Spray-Drying technique	[95]
Piperine	Piperine loaded SD	sorbitol, PEG, PVP K-30	Solvent method	[96]
Curcumin	oral nano-drug delivery system using self-nanomicellizing SD	Rebaudioside A,	Solvent Evaporation Technique	[97]

Current status and future prospects of solid dispersion based products

The solubility enhancement based on conversion of API to amorphous form is one of the widely utilized formulation approach in the last two decades and about 30% commercialized products have been developed based on it. The summary of marketed products based on SD technology is described in Table 2 [14, 34, 35, 98–101].

Table 2.

List of Marketed Formulations based on SD

Sr No	Brand name	API	Carrier	Manufacturer	Year of approval
1	Nivadil®	Nilvadipine	HPMC	Fujisawa Pharmaceutical Co., Ltd	1989
2	Sporanox®	Itraconazole	HPMC	Janssen Pharmaceuticals, Inc., USA	1992
3	Prograf®	Tacrolimus	HPMC	AstellasPharma, US Inc	1994
4	Norvir ®	Ritonavir	PVP-VA	Abbott	1996
5	Rezulin®	Troglitazone	PVP	Developed by Sankyo, manufactured by Parke-Davis division of Warner-Lambert	1997
6	Crestor®	Rosuvastatin	HPMC	Astra Zeneca	2002
7	Afeditab	Nifedipine	Poloxamer or PVP	Elan Corp, Ireland	2002
8	Cymbalta®	Duloxetine	HPMCAS	Eli Lilly	2004
9	Kaletra®	Lopinavir/ Ritonavir	PVP/VA	Abbot Labarotaries, USA	2005
10	Cesamet®	Nabilone	PVP	Meda Pharmaceuticals Inc., USA	2006
11	Nimotop®	Nimodipine	PEG	Bayer (Pty) Ltd., USA	2006
12	Fenoglide®	Fenofibrate	PEG/Poloxamer	Santarus, Inc	2007
13	Eucreas®	Vildagliptin	HPC	Novartis Pharmaceuticals	2007
14	GalvumetTM	Metformin HCL	HPC	Novartis Pharmaceuticals	2007
15	Torcetrapib	Torcetrapib	HPMC AS	Pfizer, USA	2007
16	Intelence®	Fenofibrate	HPMC	Janssen Therapeutics, USA	2008
17	Modigraf®	Tacrolimus	HPMC	Astellas Pharma Europe B.V	2009
18	Samsca®	Tolvaptan	HPMC	Otsuka Pharma	2009
19	Certican®/ Zortress®	Everolimus	HPMC	Novartis	2010
20	Onmel®	Itraconazole	HPMC	Sebela Ireland Ltd	2010
21	Incivek® (US), Incivo® (EU)	Telaprevir	HPMCAS	Vertex Pharmaceuticals	2011
22	Zelboraf®	Vemurafenib	HPMCAS	Roche	2011
23	Kalydeco®	Ivacaftor	HPMCAS/SLS	Vertex Pharmaceuticals	2012
24	Noxafil®	Posaconazole	HPMCAS	Merck	2013
25	Astagraf XL®	Tacrolimus	HPMC	Astellas Pharma Inc	2013
26	Belsomra®	Suvorexant	Copovidone	Merck	2014
27	Gris-PEG®	Griseofulvin	PEG 6000	Pedinol Pharmacal Inc	2014
28	Isoptin SR-E®	Verapamil	HPC/HPMC	Abbott Labarotaries, USA	2015
29	Orkambi®	Lumacaftor/ Ivacaftor	HPMCAS/SLS	Vertex Pharmaceuticals	2015
30	Envarsus® LCP-Tacro®	Tacrolimus	Poloxamer/ HPMC	Veloxis Pharmaceuticals	2015
31	Zepatier®	Elbasvir/ Grazoprevir	HPMC	Merck	2016
32	Epclusa®	Sofosbuvir/ Velpatasvir	Copovidone	Gilead Sciences	2016
33	Venclexta®	Venetoclax	Copovidone	AbbVie	2016
34	Stivarga®	Regorafenib	Povidone K-25	Bayer	2017
35	Mavyret™	Glecaprevir/ Pibrentasvir	Copovidone K-28	AbbVie	2017
36	Lynparza®	Olaparib	Copovidone	AstraZeneca	2018
37	Tasigna®	Nilotinib	Soluplus	Novartis	2018
38	Orilissa®	Elagolix	Soluplus	AbbVie	2018
39	Erleada®	Apalutamide	HPMC-AS	Janssen	2018
40	Vitrakvi®	Larotrectinib sulfate	HPMC-AS	Bayer Healthcare Pharmaceuticals	2018
41	Trikafta®	Elexacaftor (Crystalline)/ Ivacaftor/ Tezacaftor	HPMC, HPMC-AS	Vertex	2019
42	Symdeko®	Tezacaftor/Ivacaftor and Ivacaftor	HPMC, HPMC-AS	Vertex	2019
43	Braftovi®	Encorafenib	Copovidone Poloxamer 188	Pfizer	2020
44	Oriahnn™	Elagolix/estradiol/norethindrone acetate	PEG 3350	AbbVie	2020

With the increasing utilization and faith in SD technology, the corresponding increase in the number of patents applied and granted on the same is also rising in the recent years [102]. Extensive research have been already executed on the various aspects pertaining to SD technology [103]. The few of the recent patents related to formulations based on SD since 2019 are discussed below in Table 3.

Table 3.

Summary of Recent Patents based on Solid Dispersion

Sr no	Patent no Title & year	Summary of invention	API	SD carrier	Reference
1	US 11,202,778 B2 AMORPHOUS SOLID DISPERSIONS OF DASATINIB AND USES THEREOF 2021	The present invention describes the formation of ASD of protein kinase inhibitor Dasanitib using suitable polymeric carriers. The pharmaceutical formulation prepared thereof may be suitable for patients suffering from proliferative disorder like cancer or from diseases like H. pylori infection, achlorhydria or hypochlorhydria	Dasatinib	Eudragit L100-55 Eudragit E100 Methocel E5	[104]
2	EP 3 705 115 B1 COMPOSITION CONTAINING SELEXIPAG 2021	The present invention includes a solid dispersion containing a selective prostacyclin (PGI2) receptor agonist Selexipag and solid unit dosage form for oral administration containing API in a non-crystalline state for the treatment of pulmonary arterial hypertension. The SD are prepared by hot melt extrusion method using appropriate carrier and then incorporated into tablet or capsule	Selexipag	Copovidone, Hypromellose	[105]
3	AU 2,021,106,377 A4 MECHANISTIC APPROACH OF SOLUBILITY ENHANCEMENT: DEVELOPMENT OF HYDROTROPIC SOLID DISPERSION 2021	The present invention includes the use of novel Hydrotropic solubilization technique to improve the solubility of poor water solvency drugs belonging to NSAID category like Meloxicin and Ketoprofen for replacing the use of toxic & costly organic solvent with safe & eco-friendly hydrotropic agent. The invention also focuses on development of SD by solvent evaporation method for rapid onset of action and improved bioavailability and then further on formulation of topical analgesic gel	Meloxicin and Ketoprofen	Sodium benzoate Sodium Salicylate	[106]
4	US011103503B2 PHARMACEUTICAL COMPOSITIONS OF LURASIDONE 2021	The present invention includes ASD of slightly soluble drug Lurasidone and the pharmaceutical formulations thereof to reduce or eliminate the prior prevalent food effect along with the method of preparation of such compositions. The orally developed formulation showed better and consistent bioavailability than commercially available formulation in both fasted and fed state, along with sustaining sufficient plasma level even in fasting condition. The methods opted to develop SD is HME, Spray drying or Co-precipitation	Lurasidone	HPMCAS, HPC, PVP/VA Copolymer	[107]
5	US 11,129,815 B2 SOLID DISPERSIONS COMPRISING TACROLIMUS 2021	Tacrolimus is indicated for prophylactic action of organ rejection during Kidney transplantation as Immunosuppressant. The present invention includes SD of Tacrolimus with improved and reproducible bioavailability, SD or solid solution in hydrophilic carrier with melting point at least 2 ͦ C and pharmaceutical composition as well as solid oral dosage forms for delayed release comprising SD or solid solution. Drug release in the distal part avoids GIT related side effects as well as extensive metabolism in proximal part of GIT	Tacrolimus	Hypromellose PEG 6000 Poloxamer 188	[108]
6	US 10,874,671 B2 PHARMACEUTICAL COMPOSITIONS OF NILOTINIB 2020	The present invention covers ASD of Nilotinib fumarate or tartrate prepared by Spray Drying OR Hot Melt Extrusion and the pharmaceutical compositions developed thereof. The oral formulations showed improved bioavailability in fasting condition as there is no prominent difference in the pharmacokinetic parameters obtained with and without food	Nilotinib	HPMC-AS HPMCP 55 PVP K30 HPMC E3	[109]
7	US 10,668,020 B1 PULLULAN BASED VINPOCETINE TABLETS, LYOPLANT—TABS, AS A BUCCAL SOLID DOSAGE FORM 2020	In the current invention, Vinpocetin polymeric SD were formed by using PVP-VA 64 as carrier by lyophilization or freeze drying or solvent evaporation method. The SD was incorporated in buccal tablet containing pullulan as natural filler for the treatment of cerebral degenerative diseases to provide enhanced bioavailability by improving solubility and avoiding first pass metabolism	Vinpocetin	PVP—VA64	[110]
8	WO 2020/012498 A1 SOLID DISPERSION COMPRISING AN ANTICANCER COMPOUND FOR IMPROVED SOLUBILITY AND EFFICACY 2020	The current invention focuses on development of SD of low soluble anticancer drug with improved solubility, oral pharmacokinetics and in-vitro & in-vivo effect by solvent evaporation technique	IIIM-290	Hydrophilic SD carrier	[111]
9	US 2019/0365738 A1 AMORPHOUS SOLID DISPERSION OF VALBENAZINE TOSYLATE AND PROCESS FOR PREPARATION THEREOF 2019	The current invention discloses an ASD of Valbenazine tosylate, a process for preparation of ASD and a pharmaceutical composition comprising ASD. The ASD were prepared by Spray drying method using methanol as solvent. The spray dried ASD were incorporated into suitable oral pharmaceutical formulation	Valbenasine	HPMC Copovidone HPMC-AS PVP K-30	[112]
10	EP 3 569 225 A1 SOLID DISPERSION CONTAINING RITONAVIR 2019	The present invention describes SD of Ritonavir with a cationic polymer to suppress crystallization of drug in GIT fluid and preparation of oral pharmaceutical composition preferably tablet thereof. The composition of BCS Class IV drug Ritonavir in combination with another HIV protease inhibitor was developed to improve the bioavailability of formulation to treat HIV infection. The designed composition of film coated tablet showed better stability as compared to commercially available soft capsules	Ritonavir	Eudragit® E	[113]
11	WO 2019/220352 A1 AMORPHOUS SOLID DISPERSION OF LAROTRECTINIB SULFATE AND PROCESS THEREOF 2019	The present invention relates to the manufacturing process of ASD and the pharmaceutical compositions prepared thereof. Lorotrectinib is Tropomyosin receptor kinase inhibitor for the treatment of solid tumours. The prepared ASD improves the stability and biopharmaceutical characteristics of amorphous API. The ASD were incorporated in oral dosage forms like capsule and solution	Larotrectinib	HPMC-AS HPMC HPMCP HPC PVP K-30 COPOVIDONE	[114]

The SD technology improves the solubility of poorly aqueous soluble drugs leading to the in-vitro dissolution rate enhancement. It is fundamentally important to correlate the in-vivo bioavailability of drug with the in-vitro solubility improvement to procure the desired therapeutic efficiency of the formulation [115]. A summary of recent in-vivo studies performed on solid dispersion based formulation to achieve the corresponding pharmacological activity is discussed in Table 4.

Table 4.

Recent In-vivo studies of SD based formulations

Sr no	Active Ingredient	SD Carrier	Therapeutic Activity	Inference	Reference
1	IIIM-290	PVP K30	Anticancer	CSIR discovered anticancer lead was formulated as SD to improve solubility limited bioavailability and it showed about 1.5 times dose reduction during in-vivo study using Ehrlich solid tumor model	[116]
2	Zinc(II)-curcumin complex	PVP K30	Anticancer	The prepared SD proved to be an efficient, simplified and novel chemo-sensitizing agent for cancer treatment	[117]
3	Curcumin	HPMC	Hepatoprotective	Curcumin in ASD based formulation showed improved bioavailability, safety as well as greater potential as hepatoprotective and antioxidant in mice	[118]
4	Curcumin	PVP K30	Anti-inflammatory	Cur-PVP ASD based on molecular interaction was found to be effective to improve solubility limited bioavailability, stability and anti-inflammatory action compared to raw crystalline curcumin	[119]
5	Selaginella doederleinii	PVP K30	Anticancer	A potential ASD based anti-cancer agent with enhanced solubility & dissolution and improved bioavailability was developed that lead to considerable decrease in tumor size and micro vascular density during the in-vivo study in mice	[120]
6	( −) -Oleocanthal	( +) -Xylitol	Anticancer	OC-xylitol SD was formulated to serve dual purpose of taste masking and dissolution enhancement. It proved to be an efficient nutraceutical product to treat and prevent breast cancer during in-vivo study using xenograft mice model	[121]
7	Triacetylated andrographolide	Kollidon (VA64)	Anti-inflammatory	The SD prepared with Kollidon VA64 using HME technique showed desired dissolution profile and prevented re-crystallization of drug. It was confirmed that the SD was essential approach to improve the in-vivo anti-inflammatory action of TA	[122]

Conclusion

The solid dispersion apart from significant solubility enhancement have considerable potential in the development of different modified release formulations especially controlled and sustained release dosage forms. The availability of diversified characteristic polymers ranging from water soluble to water swellable and water insoluble plays a pivotal role in the development of SD based formulation with desired release profile as well as site specificity. The fabricated SD can be incorporated in variety of dosage forms including tablet, capsule, pellets, microspheres, films, patch or any other suitable. Many methods have been worked out where it is even possible to prepare SD laden formulation in one step process to reduce the cost and complexity of formulation development. The review article emphasizes on the vast range of approaches feasible to combine with ASD concept to develop a versatile formulation combining existing solubility enhancement benefit with the expertise of other release profile/s. Many unexplored factors are still prevalent that may hinder expected drug release from the formulation. It can also be concluded that amorphous SD is most suitable to achieve desired stability along with solubility enhancement as it reduces drug mobility within polymer matrix. Despite of tremendous work in this particular area, there is a wide scope still available in this frontier with respect to polymer and methodology selection to raise the bar. An attempt has also been made to throw light on the suitability of SD technology in the solubility improvement of natural products A current comprehensive review on solid dispersion will help to design SD based modified formulations and also discusses the current market scenario and future prospects of SD based products.

Funding

This research received no external funding.

Declarations

Conflict of interest

The authors state no conflict of interest.