Sherif Badawy

Impact of Excipient Interactions on Solid Dosage Form Stability

ABSTRACTDrug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.

A study on the effect of wet granulation on microcrystalline cellulose particle structure and performance.

PurposeThe aim of this study was to investigate the mechanism of the effect of wet granulation process on the compaction properties of microcrystalline cellulose (MCC).MethodsMCC alone and with hydroxypropyl cellulose (HPC) as a binder were wet granulated by a high-shear process using different granulation parameters (over- and undergranulated). Overgranulated batches were also ball milled after drying and compared to the unmilled material. MCC starting material and granulation were characterized for particle size distribution, surface area, porosity, and isothermal moisture uptake. Compaction behavior of the MCC and granulations was also studied using a compaction simulator.ResultsIn all cases, the wet granulation process decreased MCC primary particle porosity. Wet granulation also reduced compactibility of MCC to different degrees. Overgranulated batch with HPC showed the lowest compactibility and was less compactible than the batch without HPC granulated using the same parameters. Ball-milled material showed an increase in porosity and was significantly more compactible than the unmilled granulation from the same batch.ConclusionsThe decrease in MCC compactibility after granulation is associated with the decrease in MCC primary particle porosity and in some cases with the formation of large dense granules as well. Under certain conditions, milling seems to counteract the effect of wet granulation on MCC compactibility.

Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation.

Three model compounds were used to study the effect of process parameters on in-process critical material attributes and a final product critical quality attribute. The effect of four process parameters was evaluated using design of experiment approach. Batches were characterized for particle size distribution, density (porosity), flow, compaction, and dissolution rate. The mechanisms of the effect of process parameters on primary granule properties (size and density) were proposed. Water amount showed significant effect on granule size and density. The effect of impeller speed was dependent on the granule mechanical properties and efficiency of liquid distribution in the granulator. Blend density was found to increase rapidly during wet massing. Liquid addition rate was the least consequential factor and showed minimal impact on granule density and growth. Correlations of primary properties with granulation bulk powder properties (compaction and flow) and tablet dissolution were also identified. The effects of the process parameters on the bulk powder properties and tablet dissolution were consistent with their proposed link to primary granule properties. Understanding the impact of primary granule properties on bulk powder properties and final product critical quality attributes provides the basis for modulating granulation parameters in order to optimize product performance.

Drug Excipient Interactions

Unintended physicochemical interaction of an excipient with a drug substance in a dosage form can result in the complexation or binding of the drug, resulting in slow and/or incomplete drug release in a dissolution medium. It is important to assess the risk whether such interactions would reduce oral bioavailability of a drug from its dosage form. This chapter describes the development of a methodology to assess the biorelevance of the drug release impact of drug-excipient binding interactions using a model compound, brivanib alaninate. This methodology was developed using a combination of modeling and simulation tools as well as experimental data generated in vitro and in vivo. In addition, general application of this principle and methodology to other drug substances and binding affinities of drugs with excipients as a function of dose is described.

Role of drug substance material properties in the processibility and performance of a wet granulated product

The purpose of this study was to establish a relationship between the material properties of an active pharmaceutical ingredient (API) and its behavior during high-shear wet granulation. Using several actives and excipients as material probes, the influence of aqueous solubility, wettability, water holding capacity, mean and width of the particle size distribution, and surface area was examined. The effect of these variables on the processibility and performance of the granulations was evaluated by monitoring such responses as granule growth, compactability and flow changes upon wet granulation. The prominent findings from this study include: (a) controlled growth is highest in readily wettable APIs with low surface area, (b) uncontrolled growth is high in APIs of high solubility and low water holding capacity, (c) polydisperse granulations are produced from APIs of high contact angle and surface area, (d) improvement in compactability is high in APIs with large surface area and broader size distributions and (e) flow enhancement as a result of wet granulation is highest in APIs of large size distributions. These results are physically interpreted in this manuscript based on the prevailing wet granulation theories. Findings from this study are useful in mapping a new material to predict its performance in a high-shear wet granulation process.

Effect of Starting Material Particle Size on Its Agglomeration Behavior in High Shear Wet Granulation

The effect of anhydrous lactose particle size distribution on its performance in the wet granulation process was evaluated. Three grades of anhydrous lactose were used in the study: “as is” manufacturer grade and 2 particle size fractions obtained by screening of the 60M lactose. Particle growth behavior of the 3 lactose grades was evaluated in a high shear mixer. Compactibility and porosity of the resulting granules were also evaluated. A uniaxial compression test on moist agglomerates of the 3 lactose grades was performed in an attempt to explain the mechanism of particle size effect observed in the high shear mixer. Particle growth of anhydrous lactose in the high shear mixer was inversely related to the particle size of the starting material. In addition, granulation manufactured using the grade with the smallest particle size was more porous and demonstrated enhanced compactibility compared with the other grades. Compacts with similar porosity and low liquid saturation demonstrated brittle behavior and their breakage strength was inversely related to lactose particle size in the uniaxial compression test, suggesting that material with smaller particle size may exhibit more pronounced nucleation behavior during wet granulation. On the other hand, compacts prepared at higher liquid saturation and similar compression force exhibited more plastic behavior and showed lower yield stress for the grade with smallest particle size. The lower yield stress of compacts prepared with this grade may indicate a higher coalescence tendency for its granules during wet granulation.

Molecular Basis of Crystal Morphology-Dependent Adhesion Behavior of Mefenamic Acid During Tableting

ABSTRACTPurposeThe molecular basis of crystal surface adhesion leading to sticking was investigated by exploring the correlation of crystal adhesion to oxidized iron coated atomic force microscope (AFM) tips and bulk powder sticking behavior during tableting of two morphologically different crystals of a model drug, mefenamic acid (MA), to differences in their surface functional group orientation and energy.MethodsMA was recrystallized into two morphologies (plates and needles) of the same crystalline form. Crystal adhesion to oxidized iron coated AFM tips and bulk powder sticking to tablet punches was assessed using a direct compression formulation. Surface functional group orientation and energies on crystal faces were modeled using Accelrys Material Studio software.ResultsNeedle-shaped morphology showed higher sticking tendency than plates despite similar particle size. This correlated with higher crystal surface adhesion of needle-shaped morphology to oxidized iron coated AFM probe tips, and greater surface energy and exposure of polar functional groups.ConclusionsHigher surface exposure of polar functional groups correlates with higher tendency to stick to metal surfaces and AFM tips, indicating involvement of specific polar interactions in the adhesion behavior. In addition, an AFM method is identified to prospectively assess the risk of sticking during the early stages of drug development.

NIR chemical imaging to guide/support BMS-561389 tablet formulation development

The objective of this study was to determine whether the particle size of extra-granular tartaric acid affects the uniformity of its distribution within BMS-561389 tablets. A near-infrared imaging technique was used to assess the distribution of tartaric acid near the surface of tablet tops and bottoms. Three batches of BMS-561389 tablets were manufactured using three lots of granular tartaric acid having different particle size distributions. Near-Infrared chemical images were acquired on the tops and bottoms of 15 tablets from each lot. Spectra were collected from 1350 to 1600 nm in 10 nm increments and 16 co-added scans at each wavelength. Data were analyzed using ISys 3.1 (Spectral Dimensions, Inc.) Chemical Imaging Software. Data analysis consisted of preprocessing, principal component analysis, and image analysis of the principal component scores image. It was feasible to map tartaric acid particles near the surface of BMS-561389 tablets using near infrared chemical imaging. The tartaric acid particle size statistics based on image analysis results correlated well with pre-compaction measurements using a laser-light scattering method. The image analysis results indicate that segregation of tartaric acid between tablet tops and bottoms was apparent in tablets lots containing both the largest and intermediate-size tartaric acid particles. For tablets made with the smallest tartaric acid particles, differences between tablet tops and bottoms in either the number of tartaric acid particles or the percent tablet surface area covered by tartaric acid were not statistically different at the 95% confidence level.

Effect of processing and formulation variables on the stability of a salt of a weakly basic drug candidate.

The effect of some processing and formulation variables on the stability of tablets containing a crystalline salt of a triazine derivative was studied. The salt has a relatively low melting point and a low microenvironmental pH due to the weakly basic nature of the parent compound (pKa = 4.0). This compound decomposes through acid‐catalyzed hydrolysis. A full factorial design was used to study the effect of three variables on tablet stability: aqueous wet granulation, ball milling of the salt and filler prior to manufacturing, and the inclusion of sodium carbonate in the formulation as a pH modifier. In addition to the factorial design experiments, a batch of tablets was prepared by wet granulation, using sodium bicarbonate as the pH modifier. Stability of the drug in tablets was evaluated at 40°C/75% relative humidity (RH) and at 40°C/ambient humidity. Stability of tablets was adversely affected by wet granulation. However, stability was greatly improved by wet granulation in the presence of sodium carbonate. While sodium carbonate enhanced drug stability in the tablets, regardless of the manufacturing process, wet granulated tablets were more stable than tablets containing sodium carbonate and prepared without wet granulation. Similarly prepared tablets by using sodium bicarbonate were remarkably less stable compared with those containing sodium carbonate. The use of sodium bicarbonate as a pH modifier resulted in only marginal enhancement of tablet stability, suggesting that a higher microenvironmental pH than that provided by sodium bicarbonate is needed to maximize stability. Despite the low lattice energy of the salt and the potential for disruption of salt crystallinity by mechanical stress, milling did not appear to have an adverse effect on tablet stability under the current experimental conditions. This study shows that selection of the proper manufacturing process, in conjunction with the appropriate pH modifier, could be critical to dosage form stability.

Reversible and pH-dependent weak drug-excipient binding does not affect oral bioavailability of high dose drugs.

Objectives  Drug‐excipient binding can affect in‐vitro drug release. Literature suggests that drug‐excipient ionic binding interaction that is not disrupted by physiological salt concentration in the dissolution medium can impact a drugs oral bioavailability. We investigated whether nondisruption of interaction by physiological salt concentration was an adequate predictor of its biorelevance using the binding of a model amine high dose drug brivanib alaninate (BA) to croscarmellose sodium (CCS) as an example.