Characterization of Spray Dried Particles Through Microstructural Imaging.

Spray drying is commonly used to produce amorphous solid dispersions (ASD) to improve the bioperformance of poorly water-soluble drugs. In this study, imaging techniques such as focused ion beam-scanning electron microscopy (FIB-SEM) and X-ray microcomputed tomography (XRCT) were used to study the microstructure of spray dried (SD) particles. Spray drying at higher outlet temperature (Tout) was found to produce more spherical hollow particles with smooth surface and thinner walls, while more raisin-like particles with thicker walls were generated at lower Tout. For the first time, an artificial intelligence-facilitated XRCT image analysis tool was developed to make quantitative analysis of thousands of particles individually possible. The particle size distribution through XRCT image analysis is generally in line with what is measured by laser diffraction. The image analysis reveals envelope density as a more sensitive physical attribute for process change than conventional bulk/tap density. Further, the tensile strength of SD particle compacts correlates with the particle wall thickness, and this is likely caused by the larger interparticle contact area generated by more deformation of particles with thinner walls. The knowledge gained here can help enable SD particle engineering and drug product with more robust process and optimized performance.

pH control of nucleophilic/electrophilic oxidation.

Finding formulations that prevent degradation of the active pharmaceutical ingredient is an essential part of drug development. One of the major mechanisms of degradation is oxidation. Oxidative degradation is complex, and can occur via different mechanisms, such as autoxidation, nucleophilic/electrophilic addition, and electron transfer reactions. This paper uses three model compounds and determines the mechanisms of oxidation and strategies to reduce degradation. The mechanism of oxidation was established by comparing the results of different forced degradation experiments (radical initiation and peroxide addition), computational chemistry to those of formulated drug product stability. The model compounds chosen contained both oxidizable amine and sulfide functional groups. Although, both oxidative forced degradation conditions showed different impurity profiles the peroxide results mirrored those of the actual stability results of the drug product. The major degradation pathway of all compounds tested was nucleophilic/electrophilic oxidation of the amine to form N-oxide. Strategies to prevent this oxidation were explored by performing forced degradation experiments of the active pharmaceutical ingredient (API) in solution, in slurries containing standard excipient mixtures, and in solid formulation blends prepared by wet granulation. The reaction was significantly influenced by pH in solvent and excipient slurries, with 100% degradation occurring at basic pH values (>pH 8) and no degradation occurring at pH 2 upon exposure to 0.3% peroxide. Wet granulated blends were also stabilized by lowering the pH during granulation through the addition of citric acid prior to the solution of peroxide, resulting in little (0.02% maximum) or no degradation for the four different blends after 6 week storage at 40 degrees C/75%RH.

The development and stability assessment of extemporaneous pediatric formulations of Accupril.

Quinapril, the active ingredient in Accupril tablets, is an ACE inhibitor used to treat hypertension. Quinapril is unstable in aqueous solution and therefore the development of a liquid formulation is a significant challenge. Previous studies show the rate of degradation of quinapril into its two major degradants to be pH dependent, indicating the parent compound to be most stable in the narrow pH range of 5.5-6.5. Accupril (20 mg) and readily available pharmaceutical components were combined to generate three formulations that are stable for at least 28 days, possess acceptable appearance, and are palatable to pediatric patients. To combat the presence of magnesium carbonate in the Accupril tablets, which increase the pH of the solution above 6.5, several pharmaceutically available buffers were incorporated. Nine prototypes were developed and their characteristics evaluated after 1 week under stressed conditions. The three that most closely matched the stability criteria were chosen for a definitive stability study. A stability-indicating method was developed and validated for these studies. All three formulations met the following specifications when stored at 5 degrees C for 6 weeks; Quinapril remained >or=90% intact and the two known degradants did not reach values >or=3.0% individually or >or=5.0% combined.

Effect of added alkalizer and surfactant on dissolution and absorption of the potassium salt of a weakly basic poorly water-soluble drug.

Telcagepant potassium salt (MK-0974) is an oral calcitonin gene-related peptide receptor inhibitor investigated for the treatment of acute migraine. Under gastric pH conditions, the salt rapidly gels, then converts to an insoluble neutral form that creates an impervious shell on the tablet surface, resulting in a slow and variable release dissolution rate and poor bioavailability. Early attempts to develop a solid dosage form, including solid dispersion and nanosuspension formulations, resulted in low exposures in preclinical studies. Thus, a liquid-filled soft gelatin capsule (SGC) formulation (oblong 20) was used for clinical studies. However, a solid dosage form was desirable for commercialization. The slow dissolution of the tablet formulations was overcome by using a basifying agent, arginine, and inclusion of a nonionic surfactant, poloxamer 407. The combination of arginine and poloxamer in the formulation created a local transient basic microenvironment that promoted the dissolution of the salt and prevented rapid precipitation of the neutral form on the tablet surface to form the gel layer. The tablet formulation achieved fast absorption and comparable exposure to the SGC formulation. The final optimized 280 mg tablet formulation was successfully demonstrated to be bioequivalent to the 300 mg SGC formulation.