Structure and thermodynamics of associating solutions : prediction of phase equilibria

Ph.D.Agaram S. Abhirama

Optimizing Solvent Selection and Processing Conditions to Generate High Bulk-Density, Co-Precipitated Amorphous Dispersions of Posaconazole

Co-precipitation is an emerging method to generate amorphous solid dispersions (ASDs), notable for its ability to enable the production of ASDs containing pharmaceuticals with thermal instability and limited solubility. As is true for spray drying and other unit operations to generate amorphous materials, changes in processing conditions during co-precipitation, such as solvent selection, can have a significant impact on the molecular and bulk powder properties of co-precipitated amorphous dispersions (cPAD). Using posaconazole as a model API, this work investigates how solvent selection can be leveraged to mitigate crystallization and maximize bulk density for precipitated amorphous dispersions. A precipitation process is developed to generate high-bulk-density amorphous dispersions. Insights from this system provide a mechanistic rationale to control the solid-state and bulk powder properties of amorphous dispersions

Probing the Effect of Drug Loading and Humidity on the Mechanical Properties of Solid Dispersions with Nanoindentation: Antiplasticization of a Polymer by a Drug Molecule

Amorphous solid dispersions of clotrimazole in the polymer Kollidon VA64 were prepared as films in concentrations from 0% to 100% in 10% by weight increments. Nanoindentation was performed on each film at 18% and 49% relative humidity to assess the effect of drug loading and humidity on the mechanical properties of the solid dispersions. Although the addition of clotrimazole to the polymer reduces the glass transition temperature of the system as measured by differential scanning calorimetry, the hardness, reduced elastic modulus, and storage modulus were found to increase to values greater than those of either pure component up to drug loadings of approximately 60% by weight. Further addition of clotrimazole to the system resulted in decreased hardness and moduli with increased drug load. Dynamic vapor sorption of the dispersions shows that the hygroscopicity of the system is reduced as clotrimazole is added to the polymer

Quantifying Disproportionation in Pharmaceutical Formulations with ³⁵Cl Solid-State NMR

Reliable methods for the characterization of drug substances are critical for evaluating stability and bioavailability, especially in dosage formulations under varying storage conditions and usage. Such methods must also give information on the molecular identities and structures of drug substances and any potential byproducts of the formulation process, as well as providing a means of quantifying the relative amounts of these substances. For example, active pharmaceutical ingredients (APIs) are often formulated as ionic salts to improve the pharmaceutical properties of dosage forms; however, exposure of such formulations to elevated temperature and/or humidity can trigger the conversion of an ionic salt of an API to a neutral form with different properties, through a process known as disproportionation. It is particularly challenging to identify changes of pharmaceutical components in solid dosage formulations, which are complex heterogeneous mixtures of the API and excipient components (e.g., binders, disintegrants, and lubricants). In this study, we illustrate that ultra-wideline (UW) ³⁵Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate excipients. ³⁵Cl SSNMR can quantitatively detect the amount of PiogHCl in mixed samples within ±1 wt % and measure the degree of PiogHCl disproportionation in formulation samples stressed at high relative humidity and temperature. Unlike other methods used for characterizing disproportionation, our experiments directly probe the Cl^– anions in both the intact salt and disproportionation products, revealing all of the chlorine-containing products in the solid-state chemical reaction without interfering signals from the formulation excipients

Careful Navigation of the Crystallographic Landscape of MK-8970: A Racemic Acetal Carbonate Prodrug of Raltegravir

MK-8970 is an acetal carbonate prodrug of raltegravir (Isentress). This work presents the Merck team’s investigations into the polymorphism of MK-8970, the thermodynamic relationship between the discovered crystalline forms, and implementation of that knowledge toward solving key processing challenges. MK-8970 was found to exist in two enantiotropic polymorphs, with a crossover temperature of approximately 117 °C, as determined from solubility data. Form 2 of MK-8970, the stable form at ambient temperature, was confirmed to be a true racemic crystal form and not a conglomerate on the basis of single-crystal X-ray structure data. In preparation for scale-up of MK-8970, form control was established by mapping out solubility curves for the relevant crystalline forms in ethyl acetate as a function of temperature. Lastly an investigation of the relative solubilities of MK-8970 and a troublesome imidate impurity identified improved solvent systems for maximizing rejection of this impurity while avoiding significant yield losses