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.

Application of sorption--desorption moisture transfer modeling to the study of chemical stability of a moisture sensitive drug product in different packaging configurations.

The sorption--desorption moisture transfer (SDMT) model was used to predict the effect of desiccant quantity, tablet quantity and tablet initial moisture content on the relative humidity inside high density polyethylene (HDPE) bottles containing a moisture sensitive drug product, roxifiban tablets. The effect of these variables on the stability of roxifiban tablets in the HDPE bottles was also evaluated. There was a good correlation between the calculated relative humidity values inside the package and stability results. Tablet degradant concentration increased with the increase in the relative humidity calculated by the SDMT model. Desiccant quantity was the most important factor in controlling degradation rate, which decreased as the quantity of desiccant in the bottle was increased. For a given desiccant quantity, degradation rate increased with an increase in the weight of tablets in the bottle. The inclusion of a desiccant in the package significantly reduced the effect of initial tablet moisture content on stability. Nevertheless, the effect of initial moisture content was still discernible. This study demonstrated the practical utility of the SDMT model in understanding the correlation between packaging variables and the stability of a moisture sensitive product.

Effect of salt form on chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist in solid dosage forms.

The effect of salt form on the stability of an ester prodrug of a IIb/IIIa receptor antagonist was investigated. The pH of maximum stability for the ester prodrug is approximately 4. The mesylate salt is thought to provide lower microenvironment pH, closer to the pH of maximum stability, than the acetate salt. Stability of drug product manufactured using the mesylate salt (DMP 755) was studied and compared with that for the acetate salt (DMP 754). Formulations contained disodium citrate as a pH modifier to control formulation pH, since solid state stability for this compound is dependent on the microenvironment pH. The pH modifier was not able to achieve adequate microenvironment pH control for the DMP 754 drug product when added using a dry manufacturing process. While DMP 754 required the use of a pH modifier added in solution during wet granulation in order to improve drug product stability, DMP 755 was able to achieve similar results using the dry granulation process. Stability of DMP 755 drug product was independent of effectiveness of the pH modifier. This study showed that the choice of the salt form may provide an alternative for maximizing drug product stability.

Effect of process parameters on compressibility of granulation manufactured in a high-shear mixer.

Various processing variables that can influence granulation characteristics of a lactose-based formulation were evaluated using a Plackett-Burman experimental design. These parameters were impeller speed, granulating solution addition rate, total amount of water added in the granulation step, wet massing time, moisture content of the granulation after drying, and screen size used for the dry milling. Results showed that granulation growth was enhanced by the increase in the amount of added water, high impeller speed, and short wet massing time. On the other hand, moisture content had the largest impact on granulation compressibility, followed by the wet massing time and impeller speed. Increasing moisture content of the granulation and decreasing wet massing time or impeller speed increased granulation compressibility. Increasing impeller speed and/or wet massing time decreased granule porosity and fragmentation propensity, which led to decreased granulation compressibility. Granulation compressibility was extremely sensitive to processing conditions. Tablets from all runs showed acceptable weight variation and friability, suggesting that the parameters evaluated had little effect on these responses in the ranges tested.

Effect of drug substance particle size on the characteristics of granulation manufactured in a high-shear mixer.

DPC 963 is a non-nucleoside reverse transcriptase inhibitor with low aqueous solubility. The effect of DPC 963 drug substance particle size on the characteristics of granules manufactured by high-shear wet granulation was evaluated. The wet granulation process was used to manufacture a DPC 963 formulation with high drug loading. The formulation was manufactured using drug substance lots with different particle size distributions. Granulation particle size distribution, porosity, and compressibility were determined. A uniaxial compression test was also performed on moist compacts of the formulation prepared with different particle size distributions. Particle agglomeration behavior was affected by drug substance particle size. Granulation geometric mean diameter and fraction with particle size greater than 250 microm was inversely proportional to the drug substance particle size. Mercury intrusion porosimetry revealed higher pore volumes for the granules manufactured using the drug substance with the smaller particle size, suggesting lower tendency for granule densification than for that manufactured with the larger drug substance particle size. Granulation compressibility was also sensitive to changes in drug substance particle size. A decreased drug substance particle size led to increased granulation compressibility. Results from the uniaxial compression experiments suggested that the effect of particle size on granulation growth is the result of increased densification propensity, which in turn results from increased drug substance particle size.

Effect of different acids on solid-state stability of an ester prodrug of a IIb/IIIa glycoprotein receptor antagonist.

DMP 754 is an ester prodrug of a fibrinogen glycoprotein IIb/IIIa receptor antagonist. The purpose of this study was to determine whether the addition of acids to blends containing DMP 754 and anhydrous lactose could improve the stability at 40 degrees C/75% relative humidity. DMP 754 drug substance was stable at this accelerated condition. Blending of DMP 754 with anhydrous lactose accelerated the hydrolysis of both the ester and the amidine groups. The pH of a saturated solution of lactose is approximately 6, whereas the pH of maximum solution stability for the drug substance is approximately 4. Acids were incorporated into the blend so that the microenvironment would be more acidic and afford improved drug stability. Addition of acids decreased the rate of hydrolysis of the amidine group and this effect was more pronounced with stronger acids. However, the more acidic ingredients led to more rapid hydrolysis of the ester group.

Chemical stability of an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist in solid dosage forms.

DMP 754 is an ester prodrug of a glycoprotein IIb/IIIa receptor antagonist that undergoes ester and amidine hydrolysis in the presence of excipients. A means for the stabilization of DMP 754 was needed for the formulation of a stable drug product. Incorporation of a pH modifier in the formulation was used to control the microenvironment pH to coincide with that of maximum stability for DMP 754. Stability of tablets and capsules manufactured by (a) trituration process, (b) dry granulation process, and (c) wet granulation process was evaluated in HDPE bottles. Formulations manufactured by the dry and wet granulation processes contained disodium citrate as the pH modifier. Although aqueous wet granulation of a hydrolyzable drug is usually avoided, tablets and capsules manufactured by wet granulation were more stable in this case than those manufactured by the dry granulation process. This was attributed to the more uniform distribution of the pH modifier. Although the compression process resulted in enhanced degradation of the binary blend of DMP 754 and anhydrous lactose, tablets manufactured by the wet granulation process were more stable than capsules manufactured by the same process. Decreasing excipient-to-drug ratio enhanced the stability of tablets manufactured by the wet granulation process.