Predicting the Physical Stability of Amorphous Tenapanor Hydrochloride Using Local Molecular Structure Analysis, Relaxation Time Constants, and Molecular Modeling.

The conformational flexibility of organic molecules introduces more structural options for crystallization to occur but has potential complications, such as, reduced crystallization tendency and conformational polymorphism. Although a variety of energetically similar conformers could be anticipated, it is extremely difficult to predict the crystal conformation for conformationally flexible molecules. The present study investigates differences in thermodynamic parameters for the free base, c-FB, and an amorphous dihydrochloride salt, a-Di-HCl, of a conformationally flexible drug substance, tenapanor (RDX5791). A variety of complementary techniques such as, thermal analysis, powder X-ray diffraction (PXRD), and molecular modeling were used to assess the thermodynamic properties and the propensity of crystallization for a-FB and a-Di-HCl, tenapanor. Molecular modeling and total scattering measurements suggested that the a-Di-HCl salt exists in an open elongated state with local 1D stacking, which extends only to the first nearest neighbor, while the a-FB shows local stacking extending to the third nearest neighbor. The overall relaxation behavior, which typically is an indicator for physical stability, as measured by modulated temperature differential scanning calorimetry and PXRD suggested a nontypical dual relaxation process for the dihydrochloride salt form. The first relaxation was fast and occurred on warming from the quench conditions without any thermal annealing, while the second relaxation step followed a more traditional glass relaxation model, exhibiting an infinite relaxation time. Similar analysis for the a-FB suggested a comparatively shorter relaxation time (about 19 days) that results in its rapid crystallization. This observation is further validated with the extensive amount of physical stability data collected for the a-Di-HCl salt form of tenapanor under accelerated and stress stability conditions, as well as long-term storage for more than 3 years that show no change in its amorphous state.

Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations.

The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 °C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ∼70% RH (25 °C). Our results highlight the outcome of inadvertent drug-excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development.

Assessment of granulation technologies for an API with poor physical properties.

Granulation technologies are widely used in solid oral dosage forms to improve the physical properties during manufacture. Wet, dry, and melt granulation techniques were assessed for Compound A, a BCS class II compound. Characterization techniques were used to quantify physical property limitations inherent for Compound A including hygroscopicity, low solubility and bulk density, and poor powder flowability. High shear aqueous wet granulation induced an undesirable water mediated phase transition of the solid form. A formulation and process for dry granulation by roller compaction was developed and scaled to 10 kg batch size. Roll force, and roll gap parameters were assessed. Porosity of compacted ribbons was analyzed by mercury intrusion porosimetry, and particle size distributions of milled ribbons by sieve analysis. A roll force of 15 kN/cm produced granules with higher density and improved flow properties compared to the pre-blend. Fines content (<75 µm) decreased from approximately 90% pre-granulation to 26% post-granulation. Cohesive properties of Compound A limited drug loading (API:excipient ratio) in roller compaction to 0.6:1 or less. Hot melt granulation by extrusion assessed with four polymers. A vast improvement in drug loading of 4:1 was achieved via melt processes using low molecular weight thermo-binders (glyceryl behenate and Polyethylene glycol 4000). Granules produced by melt processing contained less fines compared to wet and dry granulation. Both roller compaction and melt extrusion are viable granulation process alternatives for scale up to overcome the physical property limitations of Compound A.

Fatty acid and water-soluble polymer-based controlled release drug delivery system.

Sustained release capsule formulations based on three components, drug, water-soluble polymer, and water-insoluble fatty acid, were developed. Theophylline, acetaminophen, and glipizide, representing a wide spectrum of aqueous solubility, were used as model drugs. Povidone and hydroxypropyl cellulose were selected as water-soluble polymers. Stearic acid and lauric acid were selected as water-insoluble fatty acids. Fatty acid, polymer, and drug mixture was filled into size #0 gelatin capsules and heated for 2 h at 50 °C. The drug particles were trapped into molten fatty acid and released at a controlled rate through pores created by the water-soluble polymer when capsules were exposed to an aqueous dissolution medium. Manipulation of the formulation components enabled release rates of glipizide and theophylline capsules to be similar to commercial Glucotrol XL tablets and Theo-24 capsules, respectively. The capsules also exhibited satisfactory dissolution stability after exposure to 30 °C/60% relative humidity (RH) in open Petri dishes and to 40 °C/75% RH in closed high-density polyethylene bottles. A computational fluid dynamic-based model was developed to quantitatively describe the drug transport in the capsule matrix and the drug release process. The simulation results showed a diffusion-controlled release mechanism from these capsules.

Comparative evaluations of powder and mechanical properties of low crystallinity celluloses, microcrystalline celluloses, and powdered celluloses.

The purpose of this study was to examine and compare the powder and mechanical properties of different batches of low crystallinity powdered cellulose (LCPC-S1 to LCPC-S5) with those of commercial microcrystalline celluloses (MCC) (Avicel PH-101, Avicel PH-102, Avicel PH-103, Avicel PH-301, Avicel PH-302, and Emcocel 90m) and powdered celluloses (PC) (Solka Floc BW-40 and Solka Floc BW-100). Both the LCPC and MCC products were aggregated powders, whereas, the PC materials showed a fibrous structure. The primary particles forming the LCPC aggregates, however, were smaller in size and showed a greater degree of coalescence between boundaries, than those forming the MCC aggregates. The LCPC materials had significantly higher bulk and tap densities and lower porosity values compared with the MCC materials. The yield pressure value calculated from the linear region of the Heckel curve for LCPC varied between 48 and 70 MPa, for Avicel and PC materials between, 80 and 106 MPa, and for Emcocel 90m was 48 MPa. These results suggest that the LCPC products and Emcocel 90m, compared with commercial MCC and PC excipients, undergo plastic deformation at relatively lower compression pressures. The total volume reduction (i.e. compressibility), determined by calculating the area under the Heckel curve (AUHC), however, was comparable for all materials, with the exception of the LCPC-S3, which owing to the low yield pressure value, showed the largest reduction in volume. With the exception of LCPC-S1 and Solka Floc BW-40, all the other materials formed compacts, whose strength ranged from about 522 to 799 MPa2. The strengths of LCPC-S1 and Solka Floc BW-40 compacts, in contrast, were 214 and 257 MPa2, respectively. Irrespective of the solid fraction levels, the LCPC compacts, in general, disintegrated much faster than the MCC and PC compacts. In conclusion, the results suggest that the new LCPC materials reported herein have powder properties that are quite different from the MCC and PC materials evaluated, and show clear potential as direct compression excipients.