Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation.

We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.

Developing In Situ Chemometric Models with Raman Spectroscopy for Monitoring an API Disproportionation with a Complex Polymorphic Landscape.

An in situ Raman method was developed to characterize the disproportionation of two salts involving a complex polymorphic landscape comprising up to two metastable and one stable freebase forms. Few precedents exist for Raman calibration procedures for solid form quantitation involving more than two polymorphs, while no literature examples were found for cases with multiple metastable forms. Therefore, a new Raman calibration procedure was proposed by directly using disproportionation experiments to generate multiple calibration samples encompassing a range of polymorph ratios through in-line Raman measurements complemented by off-line reference X-ray diffraction measurements. The developed Raman methods were capable of accurately quantitating each solid form in situ when solid concentration variation was incorporated into the calibration dataset. The kinetic understanding of the thermodynamically driven polymorphic conversions gained from this Raman method guided the selection of the salt best suited for the delivery of the active ingredient in the drug product. This work provided a spectroscopic and mathematical approach for simultaneously quantitating multiple polymorphs from a complex mixture of solids with the objective of real-time monitoring.

Insight to the thermodynamic stability of molecular crystals through crystallographic studies of a multipolymorph system.

Five solvent-free polymorphs of a pharmaceutical compound were discovered during polymorph screening. Out of the five polymorphs, only one has strong intermolecular N-H···N hydrogen bonding, whereas the others exhibit only weak C-H···N and π-π stacking interactions in addition to all the other weak C-H···X and van der Waals interactions. The relative thermodynamic stability relationships among the polymorphs are not intuitive and quite complex due to enantiotropic phase behavior. For instance, the polymorph with the most efficient packing (i.e., highest density) is not always the most thermodynamically stable form, and the polymorph with strong intermolecular interactions is not thermodynamically more stable than the polymorph with weak intermolecular interactions at all temperatures. Nevertheless, systematic examination and comparison of the molecular packing and intermolecular interactions of these polymorphs provide insight into the importance of H-bonding and packing efficiency to the thermodynamic stability of a crystalline form, and how these effects are dependent on temperature. This study seeks to correlate single-crystal structure features with experimentally established thermodynamic stability, and provides an example where a polymorph with only van der Waals forces and weak intermolecular interactions can be more stable than a polymorph that displays strong H-bonding in its structural make-up.

Introduction of a new scaling approach for particle size reduction in toothed rotor-stator wet mills.

A new scaling approach has been demonstrated for particle size reduction of an active pharmaceutical ingredient (API) in toothed rotor-stator wet mills for a wide range of wet milling conditions and scales. Compound A was crystallized by a cooling crystallization protocol in ethanol and wet milled with 2 types of lab scale mills and 1 pilot plant mill. The particle size was analyzed by FBRM (focused beam reflectance measurement), static light scattering and optical microscopy. The correlation between particle size and the energy input calculations, tailored for the toothed rotor-stator wet mill, had R(2)=0.90 on a logarithmic plot. The new scaling approach forms the basis to correlate API particle size to energy input in toothed rotor-stator wet mills by accounting for wet mill tooth configuration and geometry, rotor tip speed and the probabilistic effects of collision such as shear frequency and slurry residence time.

A new perspective on the mechanical evaluation of granular material.

The mechanical strength of granules is an important parameter to be determined prior to any further downstream formulation processing. It is important to have a good gauge on the granule integrity to forecast any foreseeable powder issues associated with the material processability such as segregation, content uniformity, and material flow-ability. In this study, a systematic methodology has been developed to quantify the integrity of these granules subjected to a low frequency acoustic field to arrive at the Granule Integrity (GI) index. This methodology has been compared to existing well-established bulk characterization techniques reported in the literature such as Heckel analysis, Kawakita analysis, and Young's modulus for four different processed samples. Heckel analysis is more amenable to examine the material deformability while Kawakita analysis is better suited to understand the mechanics of granular material. Individual granule strength measurements to determine Young's modulus often show large variations across the bulk sample. The GI index in conjunction with the Kawakita analysis provides us with more mechanistic insight and understanding into the formation of these granules from a processing perspective. This paper shows the benefits of using the GI index as a practical and direct methodology to characterize the GI of bulk samples in an industrial setting.

Process research and development for a tetrazole-based growth hormone secretagogue (GHS) pharmaceutical development candidate.

BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.

Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches.

BMS-488043 is an HIV-attachment inhibitor that exhibited suboptimal oral bioavailability upon using conventional dosage forms prepared utilizing micronized crystalline drug substance. BMS-488043 is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility of 0.04mg/mL and an acceptable permeability of 178nm/s in the Caco2 cell-line model. Two strategies were evaluated to potentially enhance the oral bioavailability of BMS-488043. The first strategy targeted particle size reduction through nanosizing the crystalline drug substance. The second strategy aimed at altering the drug's physical form by producing an amorphous drug. Both strategies provided an enhancement in oral bioavailability in dogs as compared to a conventional formulation containing the micronized crystalline drug substance. BMS-488043 oral bioavailability enhancement was approximately 5- and 9-folds for nanosizing and amorphous formulation approaches, respectively. The stability of the amorphous coprecipitated drug prepared at different compositions of BMS-488043/polyvinylpyrrolidone (PVP) was evaluated upon exposure to stressed stability conditions of temperature and humidity. The drastic effect of exposure to humidity on conversion of the amorphous drug to crystalline form was observed. Additionally, the dissolution behavior of coprecipitated drug was evaluated under discriminatory conditions of different pH values to optimize the BMS-488043/PVP composition and produce a stabilized, amorphous BMS-488043/PVP (40/60, w/w) spray-dried intermediate (SDI), which was formulated into an oral dosage form for further development and evaluation.