Characterization of Phase Separation Propensity for Amorphous Spray Dried Dispersions

Abstract

A generalized screening approach, applying isothermal calorimetry at 37 °C 100% RH, to formulations of spray dried dispersions (SDDs) for two active pharmaceutical ingredients (APIs) (BMS-903452 and BMS-986034) is demonstrated. APIs 452 and 034, with similar chemotypes, were synthesized and promoted during development for oral dosing. Both APIs were formulated as SDDs for animal exposure studies using the polymer hydroxypropylmethlycellulose acetyl succinate M grade (HPMCAS-M). 452 formulated at 30% (wt/wt %) was an extremely robust SDD that was able to withstand 40 °C 75% RH open storage conditions for 6 months with no physical evidence of crystallization or loss of dissolution performance. Though 034 was a chemical analogue with similar physical chemical properties to 452, a physically stable SDD of 034 could not be formulated in HPMCAS-M at any of the drug loads attempted. This study was used to develop experience with specific physical characterization laboratory techniques to evaluate the physical stability of SDDs and to characterize the propensity of SDDs to phase separate and possibly crystallize. The screening strategy adopted was to stress the formulated SDDs with a temperature humidity screen, within the calorimeter, and to apply orthogonal analytical techniques to gain a more informed understanding of why these SDDs formulated with HPMCAS-M demonstrated such different physical stability. Isothermal calorimetry (thermal activity monitor, TAM) was employed as a primary stress screen wherein the SDD formulations were monitored for 3 days at 37 °C 100% RH for signs of phase separation and possible crystallization of API. Powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR), and solid state nuclear magnetic resonance (ssNMR) were all used to examine formulated SDDs and neat amorphous drug. 452 SDDs formulated at 30% (wt/wt %) or less did not show phase separation behavior upon exposure to 37 °C 100% RH for 3 days. 034 SDD formulations from 10 through 50% (wt/wt %) all demonstrated thermal traces consistent with exothermic phase separation events over 3 days at 37 °C 100% RH in the TAM. However, only the 15, 30, and 50% containing 034 samples showed pXRD patterns consistent with crystalline material in post-TAM samples. Isothermal calorimetry is a useful screening tool to probe robust SDD physical performance and help investigate the level of drug polymer miscibility under a humid stress. Orthogonal analytical techniques such as pXRD, ssNMR, and FTIR were key in this SDD formulation screening to gain physical understanding and confirm or refute whether physical changes occur during the observed thermal events characterized by the calorimetric screening experiments.

Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions

“…After drying, the wet-cake was purified by three washes in hot distilled water (0.7 L each) at 70-80 C. Finally, the precipitate S C H E M E 1 Synthetic pathway in which the pulp, as starting material, was transformed in the samples used in this work. A, acetyl; HPMC, hydroxypropylmethylcellulose; S, succinoyl F I G U R E 2 (a) 13 C cross polarisation (CP) magic angle spinning and (b) 13 C CP phase inversion magic angle spinning spectra of pulp and its chemical structure. The proposed assignments are based on the previous literature.…”

“…DS (A) and DS (S) represent the degree of substitution of A and S in all polymers was placed in an 80 C oven to dry, leading a white granular solid (25.5 g). 13…”

“…[10] It is widely recognised that the polymer plays a crucial role in stabilising the ASD and that the formulation of the API and polymer into a solid dispersion prevents API crystallisation and consequently improves physical stability. [11][12][13] This is mostly due to a synergetic effect that includes increase of the glass transition temperature (T g ) of the final mixture high T g polymers (anti-plasticising effect), reducing molecular mobility of the amorphous API and the formation of specific API-polymer interactions. [14] A number of polymers have been considered as excipients in ASDs and can be classified as polyglycols (e.g., polyethylene glycol [15] and polyethylene oxide [16] ), polyvinyl (e.g., polyvinylpyrrolidone [PVP] [17] and polyvinylpyrrolidone-polyvinyl acetate [18] ) and cellulose (e.g., hydroxypropylmethylcellulose [HPMC] [19] and HPMC acetyl succinate [HPMC-AS], [20] Figure 1).…”

“…Here, we report a comprehensive NMR structural elucidation study of HMPC-AS, which provides an enhanced and more accurate assignment than those previously reported in the literature in which the 13 C NMR spectra of a range of common pharmaceutical excipients used in solid dispersion are described. [37] This is achieved by exploiting a stepwise approach relying on consecutive substitution of the HPMC polymer with acetate, succinate, and a mixture of acetate and succinate moieties, combined with acquisition of wellresolved and 1 H-edited 13 C NMR spectra and their thorough deconvolution. Additionally, it is demonstrated that it is possible to estimate the various contents of A and S directly from the experimentally obtained 13 C NMR spectra to capture the different grades of HPMC-AS.…”

“…[37] This is achieved by exploiting a stepwise approach relying on consecutive substitution of the HPMC polymer with acetate, succinate, and a mixture of acetate and succinate moieties, combined with acquisition of wellresolved and 1 H-edited 13 C NMR spectra and their thorough deconvolution. Additionally, it is demonstrated that it is possible to estimate the various contents of A and S directly from the experimentally obtained 13 C NMR spectra to capture the different grades of HPMC-AS. These results could enable more effective identification of the presence of specific-site intermolecular interactions, pinpointing which organic functionalities are involved in specific interactions.…”