Abstract
Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25°C and 60% relative humidity (RH), or under accelerated conditions, 40°C and 75% RH. Benzocaine degradation was monitored by liquid chromatography–mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25°C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions.
Key words: benzocaine, degradation, oral disintegrating tablet, platform, stability
INTRODUCTION
Orally disintegrating tablets (ODTs) have many properties that have been increasingly exploited in recent years (1). Increased patient compliance is observed with these products, particularly for geriatric and pediatric patient populations (2) and specific disease states (3,4). There is great convenience in the use of ODTs due to portability and the lack of need for water for swallowing. From a commercial standpoint, ODTs can extend product life cycle. The increased use of ODTs has led to clear guidelines for design principles and requirements. Based upon FDA recommendations (5), ODTs should disintegrate rapidly in the mouth in 30 s or less and should weigh less than 500 mg.
ODTs must be palatable, in terms of taste and mouth feel. Excipients selection is critical in reaching all of these attributes. Beyond the active pharmaceutical ingredient (API), the typical ODT composition contains an inert hydrophilic, but not hygroscopic filler (usually mannitol), a superdisintegrant or combination of disintegrants, and a lubricant. Many ready to use ODT platforms have been developed and marketed in recent years. These platforms have been designed to accelerate the formulation process for new APIs. In ODT platforms, the filler and the superdisintegrant are co-processed so that the formulator has to add only the API and the lubricant.
It is well known that the stability of the API can be affected by pharmaceutical excipients that react directly with the drug or contain reactive impurities such as peroxides, formaldehyde, formic acid, antioxidants, organic acids, and reducing sugars (6). Polyvinylpyrrolidone (PVP) excipients (povidone, copovidone, Kollidon®) often contain peroxides or other oxidative impurities like formaldehyde or formic acid. Degradation of benzocaine to N-formylbenzocaine was previously observed in aqueous PVP solutions (7).
The purpose of the present study was to evaluate API degradation within four commercially available ODT platforms using benzocaine as a model drug. The information obtained from the stability tests are useful especially in the preformulation step of drug development allowing the rationale choice of excipient mixtures for drugs prone to oxidation and hydrolysis.
MATERIALS AND METHODS
Tablets Preparation
Benzocaine USP (Parchem) was used without further purification. ODT platforms were purchased from manufacturers and used as received (Table I). The ODTs were formulated with 6% benzocaine, 1.5% magnesium stearate, and 92.5% of the respective ODT platform. Briefly, benzocaine was added to each platform and mixed for 10 min in a Turbula mixer. Magnesium stearate, a lubricant, was mixed with the powder for 5 min. Each formulation was tableted at 500 mg using 10 mm diameter concave punches on a Korsh XP1 research tableting machine under two conditions. The tablets in the first group were produced at different compression force depending on platform compressibility to create tablets with an average hardness of 100 N. The tablets in the second group were made under a constant compression force of 20 kN, which resulted in tablets with varying hardness. Tablets were evaluated in accordance with US Pharmacopoeia methods for hardness (Schleuniger Pharmatron Tablet Hardness Tester), friability (VanKel Friability Tester), and in vitro disintegration time (Schleuniger Pharmatron Disintegration Tester, Model DTG 2000).
Table I.
Components of Direct Compression Platforms
| ODT platform | PEARLITOL®Flash | Ludiflash® | PROSOLV®ODT | F-Melt® |
|---|---|---|---|---|
| Excipients | Mannitol | Mannitol | Microcrystalline cellulose | Mannitol |
| Maize starch | Kollidon CL-SF | Colloidal silicon dioxide | Xylitol | |
| Kollicoat SR 30D | Mannitol | Microcrystalline cellulose | ||
| Kollidon 30 | Fructose | Crospovidone | ||
| Crospovidone | Magnesium aluminosilicate | |||
| Dibasic calcium phosphate anhydrous |
Benzocaine Stability and Sample Preparation
Tablets were placed under International Conference on Harmonization (ICH) stability conditions (8,9) in humidity chambers at 25°C and 60% relative humidity (RH) or under accelerated conditions, 40°C and 75% RH, for up to 6 months in open pans. Following storage under the various conditions, tablets were photographed and their diameter measured using a caliper.
Two tablets, each containing 30 mg benzocaine, were ground using a mortar and pestle and dissolved in 10 mL methanol. The mixture was vortexed and undissolved excipient residue was removed by centrifuging at 1,000 rpm for 5 min. Samples (50 μg/mL) were prepared for liquid chromatography–mass spectrometry (LC-MS) analysis. To force degradation, benzocaine (12 mg/mL) was subjected to 2 N HCl (acidic stress) or 30% H2O2 (oxidative stress) aqueous solutions and stored at room temperature for 10 days. Samples (50 μg/mL) were prepared for LC-MS analysis.
LC-MS Conditions
LC-MS was performed on an Agilent 6410 Triple Quadrupole system with LC detection at 254 nm and operated in the selective ion monitoring (SIM) mode at specific mass to charge (m/z) ratios: 94, 120, 122, 137, 138, 139, 165, 166, 167, 178, 179, 180, 181, 182, 190, 193, 194, 195, 203. With this method, only the selected m/z values are detected in the analysis. The masses correspond to expected benzocaine decomposition products (7,10). Chromatographic separation of samples (10 μL) was achieved at a flow rate of 200 μL/min using a X-Bridge C8 column (2.1 × 50 mm i.d., 3.5 μm particle size) and an initial mobile phase consisting of a mixture of water (5%) and methanol (95%) acidified with 0.1% formic acid. After an isocratic hold for 1 min, the sample was then eluted with linear gradient from 95 to 5% methanol acidified with 0.1% formic acid over a period of 8 min before returning to the initial isocratic condition for 5 min. To determine the molecular formula of the detected degradation, product mass spectrometry on a Shimadzu LC-MS IT-TOF was conducted.
RESULTS AND DISCUSSION
Tablet Production and Characterization
Tablets were easily formed with each of the commercially available platforms. All tablets were white and pharmaceutically acceptable when produced at constant pressure (20 kN) and constant hardness (100 N). All tablets produced passed the friability test and were reproducible in weight. The constant pressure condition was a pressure that was above the pressure needed to compress the tablets to the desired hardness. Due to this, the disintegration time for the constant pressure tablets was consistently higher than the constant hardness tablet disintegration time (Table II). The in vitro disintegration test in a basket dissolution apparatus was conducted in water as immersion fluid to compare the different formulations. In this test, the disintegration times were above the 30-s guideline described by the NIH, but the NIH guideline defines oral disintegration time and saliva is used as immersion fluid instead of water. Dissolution times can be used to compare the preparations but does not match the conditions for the NIH definition.
Table II.
ODT Evaluation
| Platform | Properties | Disintegration time (s) | Friability |
|---|---|---|---|
| PEARLITOL®Flash | H, 100 N | 60 | Passed |
| Fc, 20 kN | 68 | Passed | |
| Ludiflash® | H, 100 N | 65 | Passed |
| Fc, 20 kN | 150 | Passed | |
| PROSOLV®ODT | H, 100 N | 420 | Passed |
| Fc, 20 kN | 600 | Passed | |
| F-Melt® | H, 100 N | 65 | Passed |
| Fc, 20 kN | 150 | Passed |
H hardness, Fc compression force
LC-MS Method Development
To validate if the LC-MS method can differentiate between benzocaine and potential degradation products, we generated degradants by subjecting benzocaine to acid hydrolysis and oxidation. Benzocaine (Fig. 1), or p-aminobenzoic acid ester (molecular formula C9H11NO2, molecular weight 165.189 g/mol), is a local anesthetic used primarily to relieve pain or irritations on the skin and mucosal surfaces. Benzocaine degradation is both acid and base catalyzed (11). Under acidic stress conditions, a peak with a retention time of 2.1 min appeared in addition to the benzocaine peak at 8.8 min (Fig. 2a). According to the SIM chromatogram (Fig. 2b), the UV peak at 2.1 min corresponds to p-aminobenzoic acid (PABA, MW 138 g/mol). PABA is the primary degradation product of benzocaine resulting from ester hydrolysis. The SIM chromatogram at m/z 138 also matches with the UV peak at 8.8 min that corresponds to benzocaine (Fig. 2d). This is most likely due to the generation of fragment ions during the mass spectrometry process. Although no corresponding UV peak was apparent, ions with a m/z of 194.2 were also identified in the SIM mode of samples that underwent acid hydrolysis. This can be explained by the increased sensitivity of the SIM mode where the mass spectrometer only collects data for specified masses rather than scanning for masses over a wide range. Following oxidation stress, degradation products eluted at 7.9 and 10.2 min (Fig. 3a) with corresponding ions at m/z = 181 and m/z = 194.3, respectively (Fig. 3b, d). It is clear from these results that the method can delineate between the parent compound and degradation products generated during acidic and oxidizing stress. Operating the LC-MS in the SIM mode further allowed us to match the retention data from UV/vis and mass spectra, which essentially gives us the molecular weight of the detected degradation product.
Fig. 1.
Structure of benzocaine and its primary degradation products, p-aminobenzoic acid, and N-formylbenzocaine
Fig. 2.
Degradation under acid conditions. a UV and b–d SIM mode MS chromatograms observed following degradation of benzocaine under acid stress. The SIM MS chromatograms of b p-aminobenzoic acid, c N-formylbenzocaine, and d benzocaine are presented
Fig. 3.
Degradation under oxidative conditions. a UV and b–d SIM mode MS chromatograms observed following degradation of benzocaine under oxidative stress. The SIM MS chromatograms of b N-formylbenzocaine, c benzocaine, and d degradation product with m/z of 181 are presented
Effect of Different ODT Platforms on Benzocaine Stability
The stability of benzocaine in four commercially available ODT platforms for direct compression was investigated under ICH conditions (8): 25°C and 60% RH and 40°C and 75% RH, for up to 6 months. No degradation of benzocaine was observed in the tablets that were exposed to subtropical conditions (25°C and 60% RH) for the entire study period of 6 months (Table III). Under accelerated degradation conditions, benzocaine decomposition was identified in Prosolv®ODT tablets (Table III). A degradation product was detected in the liquid chromatogram at 9.4 min in addition to the benzocaine peak at 8.8 min (Fig. 4). The molecular formula of the degradation product was determined to be C10H11NO3 from IT-TOF, which proposes N-formylbenzocaine as the major degradation product. The amount of degradant increased linear over time (Table III). In the forced degradation study, N-formylbenzocaine eluted at 10.2 min. This minor deviation in elution time might be explained by the absence of excipients in the forced degradation study and, hence, different column interactions or due to another product with the same molecular formula being present. In either case, it is clear that benzocaine is degrading in these formulations. Benzocaine degradation was dependent upon temperature and relative humidity, but the compression force did not affect drug stability (Table III).
Table III.
Amount of Degradation Product Within Tablets Stored Under Ambient and Accelerated Conditions. Only N-Formylbenzocaine Was Observed in Tablets. Values Are Presented as Mean ± Standard Deviation (Three Independent Samples)
| N-Formylbenzocaine (%)a | ||||||
|---|---|---|---|---|---|---|
| Time (days) | Condition | Properties | PEARLITOL®Flash | Ludiflash® | PROSOLV®ODT | F-Melt® |
| 0 | H, 100 N | ND | ND | ND | ND | |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 30 | 25°C/60%RH | H, 100 N | ND | ND | ND | ND |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 40°C/75%RH | H, 100 N | ND | ND | 0.65 ± 0.16 | ND | |
| Fc, 20 kN | ND | ND | 0.38 ± 0.04 | ND | ||
| 60 | 25°C/60%RH | H, 100 N | ND | ND | ND | ND |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 40°C/75%RH | H, 100 N | ND | ND | 1.00 ± 0.14 | ND | |
| Fc, 20 kN | ND | ND | 1.07 ± 0.13 | ND | ||
| 90 | 25°C/60%RH | H, 100 N | ND | ND | ND | ND |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 40°C/75%RH | H, 100 N | ND | ND | 1.22 ± 0.22 | ND | |
| Fc, 20 kN | ND | ND | 1.38 ± 0.51 | ND | ||
| 120 | 25°C/60%RH | H, 100 N | ND | ND | ND | ND |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 40°C/75%RH | H, 100 N | ND | ND | 2.35 ± 0.56 | ND | |
| Fc, 20 kN | ND | ND | 2.09 ± 0.63 | ND | ||
| 150 | 25°C/60%RH | H, 100 N | ND | ND | ND | ND |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 40°C/75%RH | H, 100 N | ND | ND | 2.94 ± 1.52 | ND | |
| Fc, 20 kN | ND | ND | 3.01 ± 1.52 | ND | ||
| 180 | 25°C/60%RH | H, 100 N | ND | ND | ND | ND |
| Fc, 20 kN | ND | ND | ND | ND | ||
| 40°C/75%RH | H, 100 N | ND | ND | 3.15 ± 1.96 | ND | |
| Fc, 20 kN | ND | ND | 2.82 ± 1.69 | ND | ||
ND not detected, H hardness, Fc compression force, RH relative humidity
aThe amount of degradant (in percent) was determined from the UV spectra as follows: 
Fig. 4.
Degradation products in platform P3. Representative a UV spectrum and b–c SIM chromatograms of benzocaine degradation in tablets prepared with PROSOLV® ODT. The SIM MS chromatograms of b N-formylbenzocaine and c benzocaine are presented
Drug–excipient interactions or interactions between drug and reactive impurities in excipients lead to chemical or physical interactions that adversely affect the quality of the end product. N-formylbenzocaine (Fig. 1) is most likely formed in the tablets by the reaction with formic acid. Organic acids, such as formic acid, are common impurities in poly(ethylene glycol) (PEG), hydroxypropyl methylcellulose (HPMC), povidone, and polyvinyl alcohol (6,12). Often, excipients with formaldehyde impurities also contain some formic acid due to oxidation of formaldehyde to formic acid by atmospheric oxygen. Formaldehyde contaminations exist in microcrystalline cellulose (MCC), starch, pre-gelatinized starch, crospovidone, HPMC, PEG, and lactose (6). The PROSOLV®ODT platform contains silicified MCC and crospovidone (Table I) that could be potential sources of organic acid and aldehyde impurities. The formyl and acetyl species can cause degradation of amine drugs. Similar to our observation, degradation of the smoking cessation drug varenicline was observed in tablet formulations. N-Formylation and N-methylation of the secondary amine of varenicline was attributed to the decomposition of PEG, a component of osmotic tablets, to formaldehyde and formic acid (13).
Benzocaine degradation was only observed under high relative humidity and temperature, indicating that the degradation may be related to the adsorbed water by the excipients of the formulation. When the relative humidity exceeds the excipient’s critical relative humidity (CRH), it gains moisture from that environment. The CRH of fructose, a component of the PROSOLV®ODT platform, is 64% when stored at 40°C and was thus surpassed under accelerated conditions (14). The observed degradation may be due to migration of the impurities present at high humidity conditions. This is supported for both conditions when the gross morphology of the tablets is considered.
Physical Appearance of Tablets
Although degradation of benzocaine was only detected in one platform, the physical appearance of the tablets varied greatly between the different ODT platforms, especially under accelerated conditions (Fig. 5). Mannitol, the main component of the platforms, is not hygroscopic and does not absorb water even under accelerated conditions. The disintegrants are proposed to cause the tablet’s shape changes due to their propensity to absorb water. Tablets made with PEARLITOL® Flash, Ludiflash®, and F-Melt® maintained a shiny and relatively smooth surface for the entire study period of 6 months under subtropical conditions (25°C/ 60% RH) that exist in the USA, Japan, and Southern Europe. However, after storage under accelerated degradation conditions (40°C/75% RH) for 6 months, tablets containing PROSOLV®ODT and F-Melt® were esthetically unacceptable. We did not, however, examine the physical appearance of the different formulations in the absence of the API. It is, therefore, possible that the diminished appearance of the tablets occurs without the presence of the API. It is, therefore, not possible to draw a causal relationship between the browning of the tablets and degradation of the API. However, even if the two events are mutually exclusive, they suggest that the Prosolv®ODT platform is not appropriate for the given API.
Fig. 5.
Tablet size, shape, and color. Representative photographs of the benzocaine tablets at days 0, 90, and 180 under storage (25°C/60% RH) and accelerated conditions (40°C/75% RH)
The diameter of F-Melt® tablets increased 2 and 1 mm for tablets that were compressed to a hardness of 100 N or at a compression force of 20 kN, respectively, after 6 months under accelerated conditions (Table IV). PROSOLV®ODT and F-Melt® contain crospovidone that acts as a tablet disintegrant and swells upon contact with water. Benzocaine degradation detected in PROSOLV®ODT and swelling of tablets containing F-Melt® might also partially be attributed to the increased water uptake by crospovidone under the humid conditions. Aspirin degradation has been shown to be accelerated by the adsorbed water from urea and povidone in the respective formulation (15).
Table IV.
Diameter of Tablets (in Millimeter)
| Diameter (mm) | ||||||
|---|---|---|---|---|---|---|
| Platform | ||||||
| Time (day) | Storage | Compression | PEARLITOL® Flash | Ludiflash® | PROSOLV® ODT | F-Melt® |
| 0 | N/A | H, 100 N | 10.09 | 10.34 | 10.24 | 10.14 |
| Fc, 20 kN | 10.07 | 10.22 | 10.18 | 10.08 | ||
| 90 | 25°C/60% RH | H, 100 N | 10.09 | 10.35 | 10.46 | 10.14 |
| Fc, 20 kN | 10.07 | 10.22 | 10.45 | 10.08 | ||
| 40°C/75% RH | H, 100 N | 10.15 | 10.37 | N/A | 10.34 | |
| Fc, 20 kN | 10.14 | 10.28 | N/A | 10.23 | ||
| 180 | 25°C/60% RH | H, 100 N | 10.09 | 10.35 | 10.89 | 10.14 |
| Fc, 20 kN | 10.09 | 10.22 | 10.75 | 10.08 | ||
| 40°C/75% RH | H, 100 N | 10.40 | 10.46 | N/A | 12.05 | |
| Fc, 20 kN | 10.36 | 10.41 | N/A | 11.13 | ||
H hardness, Fc compression force, RH relative humidity
Regardless of the compression condition, tablets with PROSOLV® ODT changed shape and turned yellow at 40°C and 75% RH. The discoloration of the tablets is indicative of the Maillard reaction that can occur between fructose and the primary amino group of benzocaine. Drug molecules with primary or secondary amine groups readily react with reducing sugars (16). Benzocaine may also be unstable in the presence of other reducing sugars such as glucose or lactose. The browning of vigabatrin tablets was associated with the incompatibility of the primary amine drug and a glucose impurity from MCC (17). Excipients such as MCC, starch, mannitol, and sucrose may also contain low levels of reducing sugars (6).
CONCLUSIONS
Benzocaine, a primary amine containing API, was stable in tablets that were stored at 25°C and 60% RH for the entire study period of 6 months. Degradation of benzocaine in PROSOLV®ODT tablets, which contained silicified microcrystalline cellulose, mannitol, fructose, and crospovidone, was observed under high temperature and humidity conditions (40°C and 75% RH). It is clear that ODT excipient mixtures play a significant role in the success of these formulations. When chosen wrongly, the excipient can lead to compromised stability of the API and reduced shelf life of the end product. Considering the excipient as a potential source of reactive impurities and understanding its impact on the active ingredient are essential in designing new formulations. We tested four direct compression platforms that all contained at least two different excipients. Although the excipient manufacturer strives to keep impurities low, it is also the responsibility of the user to understand the incompatibility potential between an excipient or its residues and the API, especially in those multicomponent materials. Impurities that may be problematic for a particular drug molecule might not affect other drugs. The type of dosage form (liquid or solid) and environmental factors such as temperature, humidity, and pH will affect the molecular mobility of reactive species and will thus also influence drug stability. Except PROSOLV®ODT, all the other platforms (PEARLITOL® Flash, Ludiflash®, and F-Melt®) showed chemical inertness towards benzocaine. Combining the chemical stability and physical appearance, PEARLITOL® Flash and Ludiflash® appear to have superior properties while F-Melt® was not pharmaceutically elegant and PROSOLV®ODT was an unacceptable platform for benzocaine.
ACKNOWLEDGMENTS
This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant C06 RR15482 from the National Centre for Research Resources, NIH. This research was funded in part by Roquette America, Inc. The authors would like to thank Dr. Jerry White and Bryan Zahakaylo of UIC-RRC Mass Spectrometry Facility for significant help with LC-MS.
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