Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products

Abstract

Amorphous solid dispersions (ASDs) are being employed frequently to improve bioavailability of poorly soluble molecules by enhancing the rate and extant of dissolution in drug product development process. These systems comprise of an amorphous active pharmaceutical ingredient stabilized by a polymer matrix to provide enhanced stability. This review discussed the methodologies of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Rational selection of polymers, preparation techniques with its advantages and disadvantages and characterization of polymeric amorphous solid dispersions have discussed. Stability aspects have been described as per ICH guidelines which intend to depend on selection of polymers and preparation methods of ASD. The mechanism involved on improvement of bioavailability also considered. Regulatory importance of ASD and current evolving details of QBD approach were reviewed. Amorphous products and particularly ASDs are currently most emerging area in the pharmaceutical field. This strategic approach presents huge impact and advantageous features concerning the overall improvement of drug product performance in clinical settings which ultimately lead to drug product approval by leading regulatory agencies into the market.

1. Introduction

Last two decades the new chemical entities in pharmaceutical research (NCE) are poorly water soluble and for those molecules/compounds solution formulations are often unachievable. It was reported that the Food and Drug Administration (FDA) has been approved 19 commercial ASD products in the period from 2007 to 2017 (DeBoyace, 2019; Jermain et al., 2018). When poor water solubility is the main hindrance due to the lipophilicity of a compound, formulations such as lipid-based emulsions, self-emulsifying (nano or micro) drug delivery systems (SNEDDS, SMEDDS, SEDDS), liposomes, and so on may be viable options, but their utility is limited as the drug content is typically low in these types of systems (Hamner, 2019). Biopharmaceutical Classification System (BCS) involves mathematical analysis to experimentally determine solubility and permeability of drugs (Saxena and Jain, 2019). Amorphous solid dispersions (ASDs) are being used recurrently for poorly soluble pharmaceutical compounds. In an ASD, the solubility of the drug substance is improved by disarranging its crystalline lattice to produce a higher energy state of amorphous form (Duarte et al., 2015; Elgindy et al., 2011). Polymers also play a key role to improve the solubility and bioavailability of amorphous API by drug polymer interaction. The polymer could stabilize the ASD and prevent the drug from crystallization and to provide improved physical stability under a variety of accelerated stability conditions, such as elevated temperature and relative humidity. Compared with other reported solubilization approaches, an ASD can prefer for low-solubility active pharmaceutical ingredients (APIs). ASD maintains its supersaturation in the gastrointestinal (GI) tract which is the reason for the improvement of bioavailability (Newman et al., 2015). When supersaturation is controlled, the absorption of a compound can be increased to be more than that of a saturated solution condition. Furthermore, among different crystalline forms solubility can be eliminated as they are converted to the amorphous form (LaFountaine et al., 2016). Many toxicologist and well established animal models were developed and they accepted as their polymer carriers are derived from GRAS (generally regarded as safe) excipients (Ayad et al., 2013). Usually used excipients for forming ASDs are cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hydroxy ethyl cellulose, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), methyl cellulose, chitosan, carboxymethyl cellulose, ethyl cellulose, carboxymethyl ethyl cellulose, cyclodextrin and derivatives, lactose, poloxamers, polyvinylpyrrolidone (PVP), polymethacrylates (Eudragit E, L, S, FS), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA 64), polyvinyl acetate phthalate (PVAP), and polyethylene glycols (PEG) derivatives. These polymers are biologically inactive and less absorbed in GIT (Sihorkar and Dürig, 2020). ASD are generally prepared using methods based on solvent evaporation (SE) or melt cooling. The processing technologies include spray drying (SD), hot-melt extrusion (HME), KinetiSolR dispersing (KSD), drum drying, freeze-drying (FD), rotary evaporation (RE), spray congealing, co-precipitation (CP), co-grinding, spin-coated film (SCF), centrifuge vacuum drying (CVD), supercritical fluid technology, electrostatic spinning, and microwave technology (Kumar, 2020). HME is most preferred option in pharmaceutical development because of the various advantages like favorable good powder properties, no organic solvents in the processing, small footprint of the equipment, ease of increasing batch size, feasibility and scalability from, pilot to industrial setting, and suitability of batch processing. However, requires more API hence the application of HME in discovery research is limited for screening (Bandari et al., 2020; Hwang et al., 2020). Even larger amounts of API are required for KSD and drum drying. Rota evaporation is a good choice for discovery, but it has much scale up issues for the development. Supercritical fluid technology, electrostatic spinning, and microwave technology are still under development and have yet to be proven in pharmaceutical R&D (ROTA-EVAPORATION, 2015). Freeze drying is used for water soluble API and it is not suitable for polymer carriers can only be dissolved in organic solvents. In addition, the FD process cost effective than SD, which renders FD a cost-ineffective choice for production. Nevertheless, SD is usually the technique of choice to prepare ASD in discovery stage when drug substance is only available in limited quantities (Ardeshana et al., 2020). In SD technology, wide ranges of polymers can be screened and same. The objective of this review is to comprehend current ASDs, utilization, and limits of applications. This review will discuss methods of preparation and characterization of ASDs with an emphasis on understanding and predicting stability.

2. Amorphous solid dispersion

2.1. Amorphous state (solid state details)

Amorphous pharmaceutical materials are thermodynamically metastable state and readily may convert into the more stable crystalline form. Quasi-equilibrium thermodynamic view of the amorphous form has higher solubility than crystalline form because it has a significantly higher free energy than the crystalline form (Lapuk et al., 2019a). It is illustrated that, amorphous materials are glassy nature and super cooled liquid and it can be achieved by rapid cooling. The molecular mobility is gradually reduced as the material is cooled, and the viscosity of the material increases simultaneously. This is called as glass transition temperature and state of the material called as glassy (Shekunov, 2019). However, glassy materials are metastable in nature and relative to both the equilibrium supercooled liquid and the crystalline forms of the material, and it was related to long term physical stability to be performed before the manufacture of pharmaceutical products (Hilfiker and von Raumer, 2019). The glass transition is associated with changes happened in various thermodynamic properties such as enthalpy, entropy and process volume. Also it characterized as second order thermodynamic transition (Newman and Zografi, 2020). Many literatures are available for such studies which have deals with amorphous drug delivery systems.

2.2. Amorphous solid dispersion

Bioavailability of drug can be ultimately improved by amorphous solid dispersion when drug available in amorphous form. The selection of suitable polymer carrier helps to increase rate of dissolution, enhancement of solubility of the drug and to improve the solid-state physical stability as well. A polymer carrier involved in the process of conversion of crystalline drug to its amorphous form and also it stabilizes the ASD by reducing the molecular mobility and extending its glass transition temperature (Tg). The stability of an ASD is certainly the result of disrupting intermolecular interactions in the drug’s crystal lattice and forming drug–polymer interactions. The crystal lattice nature of the drug disrupting the intermolecular interactions by polymers and it affects the stability of ASD. The thermodynamic and kinetic forces are responsible for enhancement of bioavailability of ASD (Vo et al., 2013).

The steric hindrance can create the larger surface area and it will act on crystallization inhibition and it also prevents the nucleation on crystal growth. The Noyes-Whitney equation is suitable to correlate the surface area and dissolution. As surface increases dissolution rate also simultaneously increases (Gibaldi and Feldman, 1967). The initial step of dissolution is wetting of the molecule and it can be facilitated by water soluble polymers. Even fail to achieve complete dissolution release profile, generated supersaturated solution and improved GI transit time enhances the absorption kinetics of the molecule. ASD can also improve the permeation rate by the spontaneously formed microparticles- or nanoparticles or micelles in the GI tract.

3. BCS classification

Solubility and permeability play crucial role in the per-oral drug absorption. Amidon et al. described based on dimensionless frames. BCS classification system is extensively used by the pharmaceutical industries across drug discovery and development (Charalabidis et al., 2019). The United States Food and drug administration, European medicine agency (EMEA) and World Health organization (WHO) have been accepted this proposal and using for Bioavailability bioequivalence study approval. The ICH also widely accepted BCS system for in-vitro dissolution in manufacturing quality control. Besides solubility and permeability of drug, three fundamental dimensionless numbers say absorption number, dissolution number and dose number also plays an important role (Bransford et al., 2019). Various limitations of BCS system were observed and discussed below. The BCS classification system and formulation approaches for respective class were mentioned in Fig. 1.

Fig. 1.

Biopharmaceutics classification system and formulation approaches for different classes of drugs.

4. Selection of polymers in ASD

Owing to limited drug availability at an early stage drug development, selection of suitable polymers are necessary to characterize and correlate with drugs physico-chemical properties including melting enthalpy, Tg, molecular weight, solvent miscibility and solubility, structural flexibility and viscosity of drug and polymer above and below its Tg. Though few compounds have good glass forming ability low crystallization tendency, its amorphous forms are however thermodynamically unstable. As amorphous forms are thermodynamically unstable, it was identified as good glass formers with low crystallization tendencies. Amorphous solid dispersion is incorporation of amorphous drug into the selected polymers which alter the kinetics of conversion of crystalline and super saturation of the molecule (Bhargavi et al., 2018; Trivino et al., 2019). The selection of suitable polymer determines the alteration of physicochemical properties of drugs. The selection of ideal polymer plays major roles in the dispersion are (i) it should have the ability of maintaining the drug in amorphous form not only during manufacturing also in storage and shipment as well. (ii) It should have readily soluble in GI conditions and need to maintain the supersaturated solution state which is necessary for drug absorption. (iii) it also should have an ability to improve the bioavailability by enhancing the permeation of drug through GI membranes (He and Ho, 2015).

5. Methodologies for ASD

Various preparation techniques were reported and captured in Fig. 2. Those techniques are melt fusion technique like hot melt extrusion, SCF cryogenic techniques, solvent evaporation technique including spray drying and solvent evaporation by rota evaporator, cyclodextrin-based inclusion complex techniques (co-evaporation, kneading, lyophilization/freeze-Drying technique, microwave irradiation method), electrostatic spinning, electrostatic blowing, electrospraying film casting. These techniques designed based on principles of molecular solubilizing mechanism such as micellar solubilization, complexation, increased porosity, or decreased particle size, and it should be deviated from polymer-based ASD (He and Ho, 2015). The different methods for preparing amorphous solid dispersion are discussed in this review.

Fig. 2.

Briefly captured details about ASD preparation methods and characterization methods.

List and description of some recent studies employed on ASD has been captured in Table 1.

Table 1.

List and description of some recent studies employed on ASD.

Compound name	Polymers	Method of preparation	Aim of the study	Remarks	Ref.
Vemurafenib	HPMCP HP-55, Eudragit L-100-55, HPMCAS-L	Micro-precipitated bulk powder technology	Improvement of physical stability, dissolution and human pharmacokinetic profiles	Study concluded all prepared ASD’s only Eudragit L-100-55 and HPMCAS-L ASD's were found to be stable. HPMCAS-L ASD provided better dissolution results and fivefold increased from its crystalline form	(Shah et al., 2013)
Itraconazole	Polyvinyl pyrrolidone vinyl acetate co-polymer88 and Hydroxy propyl methyl cellulose acetate succinate	Solvent evaporation	Evaluation of storage stability	Compare with PVPVA, HPMCAS showed good storage stability at extended RH more than 60% which can be attributed to its higher glass transition temperature ad lower hydrophobicity	(Zhang et al., 2019)
Phenacetin	Polyvinyl pyrollidone	Solvent evaporation	Estimation of kinetic solubility of ASD prone to crystallization	Non-linear kinetic parameters appeared on cold crystallization of Phenacetin based on molecular weight of the polymer	(Lapuk et al., 2019b)
Atorvastatin	Pluronic F127 and Pluronic F68	Fusion method	Optimization of bioavailability with reduced dose and improvement of solubility	Improvement of solubility was observed either Pluronic F127 and Pluronic F68 with 4.04 increased bioavailability compared with plain drugs	(Shaker et al., 2019)
AZD0837	Plolyethylene oxide	Hot melt extrusion	Investigation of controlled release performance of caplet shaped injection molded ASD	Study revealed that, the molecule maintained its amorphous nature throughout the dissolution process and was maintained in a super saturated state and stable as well	(Deshmukh et al., 2019)
Curcumin	Hydroxy propyl methyl cellulose E5 and Eudragit E100	Solvent evaporation	Elucidation of impact of HPMC E5 on crystallization and improvement of permeability	HPMC E5 impacts the crystallization inhibition significantly maintained the amorphous drug concentration owed to hydrogen bond interaction between the curcumin and polymer and improved the permeability by lowering of phospholipid bilayer.	(Fan et al., 2018)
Darunavir	Hydroxy propyl methy cellulose/Polyvinyl pyrollidone	Coaxial electro spraying	Introduction of coaxial electrospraying technique and evaluation of encapsulation efficiency	Study discussed about electrospraying technique and impact of polymers on molecule evaluated. Combination of these two polymers was improved the drug loading capacity and gastro resistant influence on the molecule.	(Smeets et al., 2019)
Efavirenz	Soluplus	Spray drying	Improvement of aqueous solubility and bioavailability	Experimentally obtained the phase diagrams by recrystallization of supersaturated API polymer solution. This is used to determine the temperature composition phase diagram by fast process spray drying. And employed to evaluate the different drug loadings observed with different thermal conditions	(Costa et al., 2019)
Etoposide	Vitamin E TPGS with Copovidone:Eudragit L-100 (60:20)	Solvent evaporation	Investigation of solubility and permeability interplay when using TPGS and amorphous solid dispersion	Based on experimental research, above Critical micellar concentration (CMC) solubility of Etoposide increased linearly and ASD allowed for super saturation. High level of super saturation helped via ASD improved the drug in-vivo permeability by supporting the P-gp saturation	(Beig et al., 2017)
Nifedipine	Polyvinylpyrrolidone vinyl acetate (PVP/VA 64)	Hot melt extrusion	Investigation of different types of energy input affect the stability and preparation of ASD's	Controlled instrumental parameters were selected for thermal and mechanical energy input. Found that, both mechanical and thermal energy affect the crystalline state conversion into amorphous and affected the level of mixing and degree of homogeneity in ASD as well. Author concluded thermal energy is more efficient than mechanical energy and that have better stability	(Mathers et al., 2019)
Ibuprofen	Methacrylic acid ethyl acrylate co polymer type A, Eudragit L-100-55 (EUD)	Hot melt extrusion	Evaluation of effect of heat and shear rate on physico chemical properties of drug and excipient	Preparation of binary ASD's composed of polymer and drug, minimized the level of degradation and found that stability of drug was increased further. This is because polymer and molecule subsequently buildup of sustained supersaturation state	(Mathers et al., 2019)
Griseofulvin	Polyvinyl pyrrolidone vinyl acetate polymer	Freeze drying	Evaluation of crystallization tendency of molecule on dissolution and oral absorption	Observed significant improvement in dissolution and oral absorption due to its high degree of supersaturation because of high crystallization tendency. Turbidity measurement results were revealed that, apparent phase separation concentration increased in the presence of polymers.	(Kawakami et al., 2019)
Aripiprazole	Kollidon 12 PF	Hot melt extrusion	Enhancement of solubility and bioavailability by pH modulated amorphous solid dispersion	Study revealed that, the molecule gave better dissolution results compare with plain API. However, formulations with acidifier performed much better than formulations without acidifier. It helps to improve the oral bioavailability.	(McFall et al., 2019)
Ketoconazole	Poly(vinylpyrrolidone-co-vinyl-acetate)	Hot melt extrusion	Evaluation of impact of molecular weight and PDI of polymer on drug dissolution	This study demonstrated the importance of polymers nature on formulation. Results discussed that, minute changes of molecular weight and PDI may influence supersaturation and precipitation of the drug. Controlled parameters of HME are making impact on drug dissolution.	(Auch et al., 2019)
Nevirapine	HPMCAS, hydroxypropylmethycellulose phthalate and Eudragit L100-55.	Hot melt extrusion	Evaluation of ASD with pH dependent soluble polymers to overcome limited bioavailability due to gastric pH variability	Enteric polymers were used to avoid the influence of drug in gastric environment to improve the better physical stability and dissolution performance. Solid dispersion made of enteric polymers were independent to gastric pH and exhibited superior dissolution performance	(Monschke and Wagner, 2019)
Fenofibrate	PVPK30, HPMC E6, HPMCE15	Solvent evaporation	Development of novel solid dispersion-based pellets using one step process layering method	Dissolution of pellets containing fenofibrate was found significantly higher compared with plain drug and reference compound. Bioequivalence study was conducted in beagle dogs using validated assay method. Results concluded that ASD pellets were equivalent to reference tablet.	(Nguyen et al., 2019)
Nobiletin	Mixtures of methyl hesperidin	Hot melt extrusion	Novel application of methyl hesperidin as an excipient for hot melt extrusion	Nobiletin amorphous solid dispersion was prepared using methyl hesperidin by hot melt extrusion technique. The prepared ASD was showed higher drug concentration and improved dissolution rate up to 7.5 times. Permeability of Nobiletin was predominantly increased and found that stable up to 6 months in accelerated stability conditions.	(Iwashita et al., 2019)
Rivaroxaban	Soluplus, Kollidon25 and copovidone	Melt quenching approach	Evaluation of physical stability and intermolecular interactions in polymeric carriers via thermodynamic modeling and molecular	In this study, Flory-Huggins lattice solution theory was applied to build thermodynamic phase diagrams of ASD with different polymeric carriers. Study concluded that, intermolecular interaction with moisture played important role for physical stability of prepared ASD's.	(Kapourani et al., 2019)
Felodipine	PVP K29/K32, HPMC, HPMCAS-M	Super critical fluid method	Evaluation of crystallization tendency of molecule on dissolution and bioavailability	This study concluded that, these polymers were equally effective on reduction of nucleation rate in the absence of moisture.	(Konno and Taylor, 2006)
Glibenclamide	Hypromellose acetate succinate	Anti-solvent addition method	Mechanistic elucidation of formation of drug-rich nanodroplets by dissolution	The co-spray drying method was applied for preparation of drug ASD and it significantly enhanced the dissolution which is lead to the formation of Glibenclamide rich amorphous droplets.	(Ueda et al., 2019)
Carvedilol	β-cyclodextrin and hydroxypropyl-β-cyclodextrin	Complexation and kneading technique	Enhancement of carvedilol solubility by solid dispersion technique using cyclodextrins complexation technique	Stable complexes formed which was confirmed from the complexation constant of drug and the carriers. Solid state results confirmed the carvedilol has been converted into amorphous state. In-vitro results of prepared ASD showed higher dissolution rate in phosphate buffer media with the pH range of 6.8 and 7.4 than plain drug.	(Yuvaraja and Khanam, 2014)

6. Characterization of ASD

The sound knowledge about recrystallization of ASD is required to understand the characterization and stability. Quality by Design principles demands a thorough understanding of the processes taking place at a molecular level and particle level. No single characterization technique can give the full picture of ASD and among those articles, few of them selected and highlighted in Table 2.

Table 2.

Characterization of amorphous solid dispersion with examples.

Techniques	Principle	Advantages	Limitations	Remarks	Ref.
Thermal/ Calorimetric Analysis
Differential scanning calorimetry	When a sample undergoes a physical transformation, like a phase transition, more or less heat will need to flow to it than the reference material to maintain both at the same temperature.	Suitable to measure melting, Experimental settings are simple and easily manageable	Less sensitive to heat capacity measurement	Kaushal et al. utilized to identify the glass forming ability of molecule. And they have suggested, if compounds have higher glass forming ability it has low critical cooling rates	(Kaushal and Bansal, 2008)
Modulated Differential scanning calorimetry	Uses two simultaneous heating rates - a linear heating rate that provides information similar to standard DSC, and a sinusoidal or modulated heating rate that permits the simultaneous measurement of the sample's heat capacity.	Complex and overlapping of thermal events are differentiated, Study of phase separation, accurate quantification of amorphous phases	Strongly conditions dependent, Melting: Interpretation is abstruse, measurement is not precise	Six et al. studied itraconazole-Eudragit E100 s using mDSC. They have identified drug polymer miscibility and causes of causes instability of the ASD	(Six et al., 2003)
Dynamic mechanical thermal analysis	Measurement of resultant strain that comes from the applied oscillatory stress, and it builds a function of the strain determined versus frequency or temperature	Non sample destructive technique, viscoelastic properties of polymers are fetched by time-efficient technique	Not suitable for characterizing the low viscous materials, poor stress control capacity	Yang et al. exposed the temperature dependent miscibility of acetaminophen in poly (ethylene oxide) which increased from 14% at 80 °C to 41% at 140 °C.	(Yang et al., 2011)
Isothermal micro calorimetry	The constant assessment of the heat out flow and cumulative amount of heat consumed or produced at quite constant temperature by an instance	Highly sensitive, shelf life and non-destructive process	Tedious process takes hours to days to evaluate	Gill et al. employed isothermal microcalorimetry (IMC) to procure the structural relaxation time.	(Gill et al., 1993)
Spectroscopic techniques
Solid state Nuclear Magnetic Resonance	The excitation of nuclei when bombarded with pulses of broad radio frequency radiation induces spin in nuclei and when nuclei relaxes back to their equilibrium statesthe free induction decay results or produced as response.	Non-destructive, Minimal sample manipulation, Small sample size, Simple sample preparation	Lack of sensitivity, Expensive, Difficulty of quantification-chemical noise and signal over lapping	Forster et al. utilized solid-state 1H NMR to differentiate the molecular mobility of indomethacin and nifedipine along with their ASDs. They deduced that the relaxation habits of nifedipine ASDs remarkably altered as a function of temperature, which explained the internal stability of nifedipine ASDs compared to indomethacin ASDs	(Forster et al., 2003)
Fourier transform Infrared technique	The chemical bonds and functional groups of a sample at atomic level undergoes constant rate of vibration. When IR with continuous wavelength strikes the sample, a particular wave number is absorbed by a specific bond and functional group of the sample and absorbed spectrum is produced by the detector.	Quantitative analysis, applied for all states of the matter, Nondestructive and Small sample size	less accurate results and moisture presence may give inaccurate results	Rumondor et al. used FTIR spectroscopy to investigate the degree of mixing between drugs and polymers in ASDs. Amorphous-amorphous phase separation was identified in this technique	(Chavan et al., 2017; Rumondor and Taylor, 2010)
Raman spectroscopy	It is based on Raman effect: the inelastic collisions of sample molecules when interacts with monochromatic laser beam generates the scattered light which is responsible for the construction of Raman spectrum.	Quantitative analysis, Nondestructive and Small sample size, not interfered by water, highly specific like a chemical fingerprint of a material.	The Raman effect is very weak. The detection needs a sensitive and highly optimized instrumentation; sample heating through the intense laser radiation can destroy the sample or cover the Raman spectrum.	Tres et al. employed Raman spectroscopy imaging with multivariate curve resolution real-time to explore the dissolution mechanism of ASD tablets. Homogeneity and phase separation can be identified by this technique	(Tres et al., 2014)
Microscopic and macroscopical techniques
X-ray Powder Diffraction	The filtered and collimated rays of cathode ray tube are directed towards the sample which produces constructive interference and diffracted rays which satisfies nλ = 2d sin θ (Bragg's law).	Determine crystallinity of the compound, Best method for phase analysis, non-destructive	Less interaction with lighter elements, Relatively less sensitivity	Nollenberger et al. had explained the practicability and advantages of using PXRD. He deduced that the PXRD measurements solely could not notice any difference in formulations with or without Eudragit R NE	(Nollenberger et al., 2009)
Scanning electron microscopy	Accelerated electrons in an SEM carry significant amounts of kinetic energy, and this energy is dissipated as a variety of signals produced by electron-sample interactions when the incident electrons are decelerated in the solid sample.	Three-dimensional and topographical imaging consumes less time to complete SEI, BSE and EDS analyses.	Expensive, large and must be housed in an area free of any possible electric, magnetic or vibration interference	Ye et al. utilized SEM to explore the compleX arrangement of efavirenz solid dispersions and the particle size distribution which found to be around 20 μm and uniformly distributed.	(Ye et al., 2016)
Polarized light microscopy	When polarized light hits the double refracting sample and produces ordinary and extraordinary light rays perpendicular to each other. These rays are combined using constructive and destructive interference through analyzer to produce high contrast image.	Non-destructive, easy to operate and reproducible	It is not suitable for agglomerates; sample recovery is little tedious	Telang et al. proposed that PLM might be a more appropriate tool to examine the physical stability of ASDs due to its high sensitivity when juxtaposed to XRD.	(Telang et al., 2009)
AFM	It works in three steps surface sensing, detecting and imaging, using a sharp tip cantilever to scan over the surface of a sample. The attractive and repulsive forces between the tip and the surface cause the cantilever to deflect towards or away from the surface respectively. Any of these slight deflections of cantilever are traced by deflections of laser beam which mounted on the cantilever are recorded by position sensitive photo diode and generates accurate tonographic image.	Highest lateral resolution up to 1 nm, it can identify the repeated lattices on crystal structure and good comprehensive understanding	Expensive, relatively slow scan time, which can lead to thermal drift on the sample	Matthias et al. exercised AFM technique to examine the long-term stability of solid dispersions and concluded that developed method to quantify the de-mixing by phase separation analysis.	(Lauer et al., 2011)

7. Mechanism of ASD on increasing bioavailability

In this review we are extending to discuss the drug uptake mechanism from ASD which was investigated various researchers. When ASD is contact with aqueous medium, solution state spontaneous dissolution takes place. Furthermore, API becomes micelles, crystal or amorphous suspensions and drug rich particles. Few references discussed that formation of colloidal system of ASD may induces the intestinal uptake of dissolved API (Amidon et al., 1995). Absorption of API is multi step process and those are (i) Dissolution of ASD into the dissolution media, (ii) Drug uptake from dissolved API, (iii) Equilibrium of API in dissolved API solution. Theoretically, solution state classified as crystalline stability which is API solution in maximum concentration and amorphous solubility which is API supersaturated solution with maximum concentration (Arca et al., 2017). Crystalline solubility (or could be pronounced as solubility) is a result of the thermodynamic equilibrium between an excess of crystalline solid and dissolved API in a dissolution medium, whereby strictly seen the crystalline structure should be the most stable polymorph. An amorphous solid also following the same concept in its dissolution, except that this equilibrium is metastable, i.e. is not a thermodynamic equilibrium, and it exists between the amorphous state of the drug and its solution form in the absence of any crystalline material. If a supersaturated drug solution exceeds the amorphous solubility, this amorphous phase will form spontaneously. Amorphous liquid phase separation is defined as drug rich particles are metastable in nature and crystallization occurs spontaneously. Amorphous compounds have desired properties of higher apparent solubility than their crystalline state owing to their higher energetic state and the disordered structure that does not require the crystal lattice to be broken while dissolution. In contrast to the crystalline form of a drug, the amorphous form is in a state of higher energy. This is because amorphous state holds excess thermodynamic properties such as enthalpy, entropy and Gibbs free energy. The continuous change in free energy acts as driving factor for recrystallization. The difference in Gibbs free energy between the amorphous and the crystalline states can be calculated using enthalpic and entropic values for the amorphous and crystalline state as shown below equation.

$$G_{conf}=H_{conf}(T)+S_{conf}(T)$$

The term “configurational” denotes the difference between the amorphous and the crystalline state and the parameters Hconf and Sconf may be calculated from their relationship with the heat capacity. The higher the configurational values are the greater are the differences between the crystalline and the amorphous states (Graeser et al., 2010).

The formation of dissolved ASD is crucial step for the improvement of dissolution profile of drug and it is directly linked with bioavailability. Craig and Simonelli established the carrier based and controlled drug release of API of ASD polymer mixture. They have proposed two concepts and those are followed. If the polymer is does not dissolved in dissolution medium, it forms a viscous layer, and this will be limiting the drug release from carrier. And the same way, the polymer is completely dissolved in dissolution medium, it is less chance to form the viscous layer and predominantly dissolution is drug controlled (Craig, 2002; Simonelli et al., 1969). There is evidence in the published literature, mainly-three mechanisms are involved in dissolution of ASD (Schittny et al., 2020).

7.1. Carrier controlled release

Dissolution media entrapped into the polymer matrix and induces the formation of viscous gel layer, which the drug molecule can diffuse to the media. This is usually slow process and concentration of drug is controlled by API in ASD and volume of dissolution media (Dahlberg et al., 2010; Indulkar et al., 2017; Punčochová et al., 2015).

7.2. Dissolution controlled release

Simultaneously API reaches the super saturation level, as the API and polymer released in the medium and this fastens the dissolution process. The supersaturation concentration is controlled by total drug in ASD and volume of dissolution media.

7.3. Drug controlled release

The polymer and drug dissolves in dissolution media and but amorphous API of ASD dissolves in controlled rate. But in this mechanism, there is a chance drug to get crystallization during dissolution and this may happen if amorphous form of drug is stable enough. Above discussed mechanisms were depicted in Fig. 3.

Fig. 3.

Basic concept of drug uptake from ASDs. From the solid state of ASDs containing polymers, micelles, crystals and complex mixture of API in solution and colloidal API emerges, from which the drug absorption through the intestinal membrane is enhanced. And followed by three main concepts for dissolution from ASDs were depicted.

8. Stability of amorphous solid dispersion

Amorphous solid has short order arrangement of molecules in comparison with crystalline solids which is arranged in three-dimensional array. Amorphous solids have ideal pharmaceutical properties of greater solubility and higher kinetic solubility when compared with its crystal form. In in-vivo a well-developed amorphous system can exist in super-saturated form, and thus enhancing the exposure of the drug. Amidst of all these assets of ASD the major liability is their poor physical and chemical stability which often rise challenges in the development of commercialization of the product (Miller et al., 2012; Tran et al., 2011). The major causes of the instability of the product are due to 1) Scarce of promising technologies to prognosis the stability of formulation, 2) depletion in understanding physiochemical properties of API, additives and polymers, 3) dearth of prejudice on technologies to setup for manufacturing. To curtail imperils of physical instability these factors should be considered.

There are many approaches were available to discuss the mechanistic insights and instability of ASD which was prepared by various techniques. The traditional approach for the prediction of stability is predicting stability under stress conditions as per ICH guidelines. Typically long term stability will give a clear picture of ASD formulation with respect to solid-state properties as well as physical and chemical integrity (Six et al., 2004). As per ICH Q1 guidelines common set of stress conditions would generally include 2–8 °C refrigerated, 25 °C/60% RH, 30 °C/65% RH, 30 °C/75% RH, 40 °C/75% RH with time points ranging from one day up to six months or two years. At every time point under each stress condition, the sample is analyzed using XRPD, DSC, and/or FTIR as depicted above. In the late-phase drug development, long-term stability is carried out for years to confirm the shelf life by either PXRD or DSC. In this case, the objective is not to predict but to estimate real-time stability (Committee, 2003)). In addition to the stability assessment of ASD with the goal for drug product development, the ASD formulation also needs to sustain supersaturation during the in vivo dissolution testing to achieve the solubility improvement and to optimize drug absorption. In case of preclinical animal studies, suspension stability may also be important. The ASD stability is conducted to support pharmacokinetic and/or toxicology studies. The preferred suspension vehicle is the one in which the API would remain amorphous for up to 4–6 h at room temperature (Nagapudi and Jona, 2008; Newman et al., 2015).

8.1. Factors affecting stability

The spontaneous conversion of ASD back into more stable crystalline form can be observed in meta-stable sate of ASD. The specific interactions between the drug and the polymers can lead to the reduction of molecular mobility and molecular coupling which acts as appended causes for the conversion of amorphous to crystalline form. The factors which plays prominent role on thermodynamic (responsible for nucleation and crystal growth) and kinetic (molecular mobility) aspects are processing and storage conditions, parameters such as temperature and relative humidity (RH) (Korhonen et al., 2008; Wegiel et al., 2013).

8.2. Thermodynamic aspect

The solid-state changes will be observed on molecular level when ASD is considered as a glassy solution of poor soluble drug in hydrophilic polymer having high glass transition. As thermodynamic driving force is responsible for the crystallization is inversely proportional to the rate of temperature decreasing and kinetic aspect. This literally means, the boost in the thermodynamic force with increased rate of supercooling then, there is increase in the kinetic barrier to crystallization and decrease in molecular mobility (Liu et al., 2020).

A mass of crystalline material is attained by crystal growth after the formation of stable nucleus through the thermo dynamic driving force of nucleation (Moseson et al., 2020). The crystal growth diffuses from bulk solution into the interface, which often described by the equation:

$$u=\frac{k}{\delta }[1-\text{exp}(\Delta G∕RT)]$$

8.3. Kinetic Aspect: Molecular mobility

The API re-crystallization in solid dispersion can be prevented extensively by kinetic stabilization of the product. The molecular mobility has a great impact in stabilization which holds the rotational and transitional movements of the molecule and allows the molecule to diffuse surface integration (Kapourani et al., 2020; Monschke et al., 2020).

8.4. Effect of temperature on molecular mobility

Temperature has its own stance on the stability of ASD as crystallization is a function of temperature. The rapid phase separation and crystallization of ASD takes place when there is a transition of glass phase to the liquid phase at elevated temperature above Tg (Lapuk et al., 2019b). Usually, as per the Tg – 50 °C rule, the ASD are recommended to store at least at a temperature 50 °C less than its Tg. But it is not applicable for ASD when crystallization is due to α-relaxation. On the flipside there is another possibility to store the ASD at a temperature where molecular mobility can be ceased entirely is known as Kauzmann temperature (Tk) (Blaabjerg et al., 2019; Martinez-Garcia et al., 2014).

8.5. Moisture effect on mobility

The ASD stability is greatly influenced by the presence of moisture in the interactions between the moist and API or the polymer. Those interactions are of two types: absorption and adsorption of water molecules at bulk or surface levels. As amorphous forms have higher kinetic solubility than crystalline forms so it absorbs more water when compared to crystalline form (Rumondor et al., 2011). Water in the ASD exhibit the plasticizing effect which lowers the transitional temperature of the ASD and further increases the rate of crystallization. Plasticizers affect the various parameters in the system by decreasing the strength, viscosity transitional temperature and increase in molecular mobility which eventually increases physical and chemical instability (Li et al., 2020).

The polymers also elicit the plasticizing effect when comes in contact with water or moisture by forming the hydrogen bond between the water, polymer and API and affects the mobility of the dispersed API. These can be traced by employing Fourier Transform(FT), near infrared techniques, and differential scanning calorimetry (DSC) (Chavan et al., 2017).

9. Regulatory considerations in development of ASD

Amorphous solid dispersion (ASD) provides a scope to improve the bioavailability and therapeutic efficiency by enhancing the physicochemical properties like solubility of poorly aqueous soluble drugs. On the other side, manufacturing cost is very less compare to the other approaches such as such as cosolvent or self-emulsifying drug delivery system (SEDDS) and an unacceptable level of surfactants and/or solvents, which will not be acceptable to regulatory authorities (Ivanisevic, 2010). This is a major challenge for the pharmaceutical companies to maintain the drug in the amorphous solid form in the solid dispersion with respective to meet the quality specifications parameters and to ensure expected in vivo performance. The major challenge is unfortunately final dosage forms undergoes devitrification especially which the compound has low therapeutic dose such as tacrolimus 0.4 mg (Janssens and Van den Mooter, 2009). Because of product ages during storage period, it fails to maintain the regulatory specifications such as dissolution, crystallization tendency and percentage purity of various regulatory bodies. Additionally, low-dose drugs also have manufacturing issues like blending and content uniformity. In the past experience, various ASD products were recalled by FDA due to safety and efficacy issues (Guo et al., 2013; Sihorkar and Dürig, 2020). Quality by design (QbD) is a new drug product development platform where quality is a matter of final product rather than confirmed by quality control analytical tests. In QbD critical quality attributes (CQA) is used to understand, control and monitor the critical manufacturing steps by utilizing new technologies and mathematical tools (multivariate analysis). A generic product is the therapeutic equivalent or copy-cat version of the original drug product, reference listed drug (RLD) approved by the FDA. Generic drug manufacturers showing interest to prove their product is pharmaceutically equivalent and bioequivalent, and hence therapeutically equivalent to the RLD (L Chaves et al., 2014). The current good manufacturing practices (cGMP) followed for every drug product and those should also be labelled appropriately and manufactured with fulfilment of compliance. Since (New drug application) NDA has already set up the safety and efficacy of the drug, the Abbreviated New Drug Application (ANDA) sponsor need not to repeat safety and efficacy studies. The data requirement for filing NDA and ANDA include chemistry, manufacturing, controls, testing, and labelling. This is the responsibility of the ANDA sponsors to show that their product meets the same quality standard as that of RLD (FDA, 2007; Food; Food and Administration, 2013).

9.1. Quality by design

The traditional approach of pharmaceutical development may be called quality by testing (QbT) this approach is based on the assumption that tighter specific parameters will be able to detect changes in the formulation and process parameters among batches. Quality is a main concern for regulatory authorities and it is necessary to develop the stringent guidelines to ensure the product specifications till that validity of drug product (Rathore and Winkle, 2009). This newer approach is called quality by design (QbD) as defined by ICH Q8 (R2) document “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” (Guideline, 2009). Information gained through QbD helps in establishing design space, specifications, and manufacturing controls. The element of QbD include quality target product profile, risk assessment, critical quality attributes, drug substance, polymers and/or excipients, amorphous/crystalline ratio, dissolution, manufacturing process, quality risk management, design space and control strategy (Kepert et al., 2016).

9.2. Critical quality attributes

As per ICH-Q8 (R2) critical quality attribute (CQA) is defined as “physical, chemical, biological, or microbiological characteristic that should be within the appropriate limit range or distribution to ensure the desired product quality”. In general, CQAs are considered to be ascribing of the drug substance, excipients (polymers), and final drug products but might also include CQA of the drug product intermediates in various manufacturing steps. The CQAs of a drug product may include those characteristics that affect purity, dose strength, drug release profile, and storage stability, e.g., assay, impurity profile, accelerated stability, dissolution rate, and amorphous/crystalline (A/C ratio), etc. More specifically, for ASD, important CQAs are dissolution and A/C ratio. This is directly influencing the shelf life of the final product. Intermediates ASD could be primary granules containing a solid dispersion of drugs and polymers and/or excipients before blend with other ingredients of the formulation such as diluents, lubricants, and glidants, etc. to formulate stable solid dosage forms such as tablet and capsule (Charoo and Ali, 2013; Fonteyne et al., 2013; Fonteyne et al., 2014).

9.3. Drug substance

The properties of drug substance should be carefully assessed. Based on drug substance properties the excipients, method, and process selection for ASD product will be evaluated. The properties to be considered are solubility and miscibility in organic and aqueous solvents, interaction with polymers, melting point, particle size and distribution, micromeritic properties, and thermal stability. These properties determine manufacturing ability, product performance, and long-term storage stability. For example, hot melt extrusion and spray drying cannot be used for thermally labile drug molecules (Forster et al., 2001).

9.4. Polymers/Excipients

Polymers play a major role in ASD formulations and it should meet regulatory requirements. They should be falls in the category of food or pharmaceutical-grade materials which is considered “Generally Regarded As Safe” (GRAS) category. At FDA inactive ingredient database, list of safe excipients/polymers and their percentage level of safely has mentioned (Food and Administration, 2017). The suitable polymer selection is depending on physicochemical properties of the drug, manufacturing process, and its manufacturability as it is one of the determinants of CQAs of the ASD. The polymer properties also to be concerned as a component of the ASD formulation are polymer type, molecular weight, polydispersity nature, concentration or amount, number of the polymer in the formulation, melting point and/or glass transition temperature (Tg), drug miscibility, solvent solubility, particle size and distribution, hygroscopicity, compatibility with the drug and other excipients of the formulation, presence or absence of the intermolecular interactions (chemistry of the polymer), mechanical properties and chemical stability (Al-Obaidi et al., 2009). Drug to polymer ratio is selected based on polymer properties and it should be convenient to process and allow for the intermediate also to be processed into tablet or capsule dosage form. The biggest task of a solid dispersion is to maintain the drug in the amorphous state in the final dosage form. This can be attained by using low drug strength and high polymer levels. On the other hand, physicochemical interaction to be taken in account to avoid unexpected outcomes of dosage form at the final level as thermodynamics of crystallization/destabilization driving forces depend on the drug loading capacity, drug–polymer solubility and miscibility, and its glass transition (Tg) (Baldrick, 2013).

9.5. Amorphous/Crystalline ratio (A/C ratio)

Proven in vivo/in vitro performance of the ASD drug product is due to the availability of drug is in completely or partially amorphous drug in these products when compared to its crystalline form drug product. Additionally, in vivo performance of the ASD may be related to A/C ratio and keeping that ratio entire of its shelf life would ensure persistent pharmacological response. Hence, it is necessary to understand the formulation and process parameters that could possibly conversion of A/C ratio in the final product (Rahman et al., 2014). Meanwhile, monitoring of this ratio is also crucial during drug product development as it can affect the formulation and/or process factors need to change and control. By the same way, post approval monitoring of the ratio is also important as it can estimate when product becomes unsafe/inefficacious to use. It may cause recalling of drug products from market. The various analytical tools were available to monitor the A/C ratio on various level of manufacturing and post marketing process. This is one of the specifications of ASD-based products in NDA/ANDA submission to the USFDA as a measure of safety and efficacy of the product. Powder X-ray diffraction (PXRD) is the golden technique used to identify and quantify the crystalline drug in the amorphous system. The technique is very simple to handle and non-destructive, with the ability to identify crystallinity at the level as low as 5%. As crystalline material shows strong diffractions with respective of their molecular arrangement in the crystalline lattice, but amorphous material shows an amorphous halo and diffuse diffraction pattern due to lack of crystalline order at the molecular level (Bhargavi et al., 2017; Shah et al., 2012). For ASD, intermediate product is well mixed with other excipients of the formulation, which is leading to determination of the A/C ratio, especially for the low-dose drug. Apart from PXRD other techniques of spectroscopy such as Fourier infrared, near infrared, or Raman spectroscopy in conjunction with chemometric methods such as principle component analysis and partial least square analysis, which may use to predict and segregate the peaks of the drug from the excipients (Zidan et al., 2012).

9.6. Design space

According to ICH Q8 (R2) document, design space is “a multi-dimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality”. Working within design space is not concluded a change of parameters because product will meet the defined quality. However, any parameter moved out of the design space is considered as change and it initiates regulatory post approval process. The design space is wider nature and robust to use, as it would accommodate wider variation in the process and/or formulation parameters. Risk assessment, multivariate experimental design, literature, and prior experience/knowledge contribute in defining the design space (Evans et al., 2019). Design space of the product can be prepared through complex mathematical relationships. The process parameters studied should be CPPs that have significant effect on the CQAs. On other side, material attributes studied should be critical attributes of the drug substance (particle size, polymorphs, impurity, etc.) and excipients (moisture level, particle size, molecular weight, etc.) that would affect the CQAs of the ASD. CPPs help in defining and controlling the design space. Practically, it may be easier to understand, develop and control design space of individual unit processes of a multistep operation, and this approach would also provide greater operational flexibility (Mishra et al., 2018). Various marketed products of ASD were captured in Table 3.

Table 3.

Examples of commercially available medicines using solid dispersion technologies.

Product name	Drug	BCS class	Carrier polymer	Preparation method	Company name	Therapeutic category	Dosage form	Year of approval in FDA	Ref.
Cesamet (US)/CanemesAustria)	Nabilone	II	PVP	Solvent evaporation	Valeant	Cancer	Capsule	1985	(Food and Administration, 2006)
Onmel	Itraconazole	IV	HPMC	HME	Merz	Onychomycosis	Tablet	2010	(Gupta et al., 2013)
Advagraf/ Astagraf XL	Tacrolimus	II	HPMC	Wet granulation	Astellas	Organ transplantation	Capsule	2013	(Noble et al., 2018)
Gris-Peg	Griseofluvin	IV	PEG 6000	Melt extrusion	Pedinol	Fungal infection	Tablet	1975	(Chiou and Riegelman, 1970)
Crestor®	Rosuvastatin	II	HPMC	Spray drying	Astra Zeneca	Hyperlipidemia	Tablet	2002	(Vo et al., 2013)
Cymbalta	Duloxetine	II	HPMCAS	Not available	Eli Lilly	Depression and Anxiety	Capsule	2004	(Bymaster et al., 2003)
Kaletra	Lopinavir/ ritonavir	IV	PVP	PME	AbbVie	AIDS	Tablet	2005	(Corbett et al., 2002)
Eucreas/ Galvusmet	Vildagliptin/ Metformin HCL	III	HPC	Melt extrusion	Novartis	Diabetes	Tablet	2007	(Lu et al., 2014)
Intelence	Etravirine	IV	HPMC	HME	J & J	AIDS	Tablet	2008	(Abramowicz et al., 2008)
Prograf	Tacrolimus	II	HPMC	Kneading, drying	Astellas	Organ transplantation	Tablet	1994	(Woillard et al., 2011)
Samsca	Tolvaptan	IV	N/A	Granulation	Otsuka	Hyponatremia	Tablet	2009	(Ramesh et al., 2015)
Certican/ Zortress	Everolimus	III	HPMC	Co-precipitation	Novartis	Organ transplantation	Tablet	2010	(Ardeshana et al., 2020)
Lozanoc	Itraconazole	IV	HPMCP	Spray drying	Mayne	Fungal infection	Capsule	2012	(Pérez-Ruiz et al., 2002)
Fenoglide	Fenofibrate	II	PEG6000, Poloxamer 188	Controlled agglomeration, SD	SantorusVeloxis	Hyperlipidemia	Tablet	2007	(Ling et al., 2013)
Norvir	Ritonavir	IV	PVP	HME	Abbvie	AIDS	Tablet	2010	(Schouten, 1996)
Incivek	Telaprevir	II	HPMCAS	Spray drying	Vertex	Hepatitis	Tablet	2011	(Kwong et al., 2011)
Zelboraf	Vemurafenib	IV	HPMCAS	Microprecipitation	Roche	Cancer	Tablet	2011	(Shah et al., 2013)
Kalydeco	Ivacaftor	II/IV	HPMCAS	Spray drying	Vertex	Cystic fibrosis	Tablet	2012	(GUNTAKA and LANKALAPALLI, 2019)
Noxafil	Posaconazole	II	HPMCAS	SD, HME	Merck	Fungal infection	Tablet	2013	(Hens et al., 2016)
Viekira™ (US)/Viekirax® (EU)	Ombitasvir/Paritaprevir/Ritonavir	II	HPMCAS/TPGS/ Propylene Glycol Monolaurate	Melt extrusion	Abbvie	Heapatitis C	Tablet	2014	(Solanki et al., 2019)
Isoptin SR	Verapamil HCl	II	HPC/HPMC	HME	Abbott	HTN	Tablet	1997	(Vajna et al., 2011)
Mesulid fast	Nimesulide	II	B-CD	β-CD	Novartis	Pain	Tablet	Not filed	(Patel, 2016)
Rezulin	Troglitazone	II	HPMC	HME	Pfizer	Diabetes	Tablet	1997	(Ito et al., 2010)
Sporanox	Itraconazole	IV	HPMC	Spray drying	Janssen	Fungal infections	Tablet	1992	(Thiry et al., 2017)

10. Future aspects and conclusion

Much pharmaceutical industry has evolved rapid use of ASDs for addressing bioavailability issues associated with low solubility API. The main confront remains in ASD is chemical or physical stability with limited data. Looking for solid state nature of solid i.e. crystalline or amorphous by XRPD or DSC is not effective means of ASD analysis since it only estimates instability; it does not predict it. Many researches are ongoing for prediction and characterization of ASD compositions can quickly be screened and lead formulations chosen that will reduce physical or chemical stability issues. With this protocol in place, there may be a driver for many conventional formulations to switch to ASDs merely for robustness purposes. Formulating amorphous API and associated concerns with molecular and particle attributes changes may become obsolete, or at the very least, a fewer effective means of quickly getting drugs on the market. Introduction of QbD principles as laid out in the ICH documents Q8, Q8 (R2) and Q9 allow for a rational drug product development with well-controlled product intermediate and final product quality in the QbD paradigm. Solid dispersion products are highly amenable to the utilization of novel technologies with respect to the drug crystalline reversion and content uniformity throughout the shelf life.