Abstract
This technical note investigated the loss of dissolution rate during accelerated stability studies with a dry blend capsule formulation containing an amorphous salt of drug NVS-1 (Tg 76°C). After 6 m at 40°C/75%RH, dissolution of NVS-1 was ≤40% of initial value. Scanning electron microscope characterization of the undissolved capsule contents from samples stored at 50°C/75%RH for 3 weeks showed agglomeration with a distinct “melt and fuse” morphology of particles. At elevated temperature and humidity conditions, undesired sintering among the amorphous drug particles was observed. Humidity plasticizes the drug as the stability temperature (T) gets closer to the glass transition temperature (Tg) of the amorphous salt (i.e., smaller Tg-T); a decreased viscosity favors viscoplastic deformation and sintering of drug particles. When moisture is adsorbed onto agglomerated drug particles, partial dissolution of the drug forms a viscous surface layer, further reducing the rate of dissolution media penetration into the bulk solid, hence the slower dissolution rate. Formulation intervention focused on the use of L-HPC and fumed silica as disintegrant and glidant and the removal of the hygroscopic crospovidone. Reformulation improved dissolution performance at short-term accelerated stability conditions of 50°C (± 75%RH); however, sintering to a lesser extent was still observed at high humidity, impacting the dissolution rate. We infer reducing the impact of moisture at high humidity conditions in a formulation with a 34% drug load is challenging. Future formulation efforts will focus on the addition of water scavengers, reducing drug load by ~50% to physically separate drug particles by water-insoluble excipients, and optimizing disintegrant levels.
References
Greco K, Bogner R. Crystallization of amorphous indomethacin during dissolution: effect of processing and annealing. Mol Pharm. 2010;7(5):1406–18.
Alonzo DE, Gao Y, Zhou D, Mo H, Zhang GGZ, Taylor LS. Dissolution and precipitation behavior of amorphous solid dispersions. J Pharm Sci. 2011;100(8):3316–31.
Meulenaar J, Beijnen JH, Schellens JHM, Nuijen B. Slow dissolution behaviour of amorphous capecitabine. Int J Pharm. 2013;441(1–2):213–7.
Puri V, Dantuluri AK, Bansal AK. Investigation of atypical dissolution behavior of an encapsulated amorphous solid dispersion. J Pharm Sci. 2011;100(6):2460–8.
van Drooge DJ, Hinrichs WLJ, Frijlink HW. Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions. J Cont Rel. 2004;97(3):441–52.
Qian S, Wang v, Li Z, Wang X, Ma X, Liang S, et al. Charge-assisted bond N+-H mediates the gelation of amorphous lurasidone hydrochloride during dissolution. Int J Pharm. 2017;518(1–2):335–41.
Hayakawa E, Furuya K, Kuroda T, Moriyama M, Kondo A. Studies on the dissolution behavior of doxorubicin hydrochloride freeze-dried product. Chem Pharm Bull. 1990;38(12):3434–9.
Heng W, Wei Y, Xue Y, Cheng H, Zhang L, Zhang J, et al. Gel formation induced slow dissolution of amorphous indomethacin. Pharm Res. 2019;36(11):159.
Han J, Li L, Pang Z, Meiling S, He X, Qian S, et al. Mechanistic insight into gel-induced aggregation of amorphous curcumin during dissolution process. Eur J Pharm Sci. 2022;170:106083.
Fan C, Pai-Thakur R, Phuapradit W, Zhang L, Tian H, Malick W, et al. Impact of polymers on dissolution performance of an amorphous gelleable drug from surface-coated beads. Eur J Pharm Sci. 2009;37(1):1–10.
Hartmann M, Palzer S. Caking of amorphous powders - material aspects, modelling and applications. Powder Tech. 2011;206(1–2):112–21.
Kamyabi M, Sotudeh-Gharebagh R, Zarghami R, Saleh K. Principles of viscous sintering in amorphous powders: a critical review. Chem Eng Res Des. 2017;125:328–47.
Fox TG. Influence of diluent and of copolymer composition on the glass temperature of a polymer system. Bull Am Phys Soc. 1956;1:123.
Soundaranathan M, Vivattanaseth P, Walsh E, Pitt K, Johnston B, Markl D. Quantification of swelling characteristics of pharmaceutical particles. Int J Pharm. 2020;590:119903.
Desai PM, Liew CV, Heng PWS. Review of disintegrants and the disintegration phenomena. J Pharm Sci. 2016;105(9):2545–55.
Mishra SM, Sauer A. Effect of physical properties and chemical substitution of excipient on compaction and disintegration behavior of tablet: a case study of low-substituted hydroxypropyl cellulose (L-HPC). Macromol. 2022;2(1):113–30.
Acknowledgements
The authors acknowledge Ping Li, Frances Liu, Marilyn Alvine, Gregory Argentieri for assistance with design of experiments and material characterization.
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The authors have approved the contents of this manuscript and are accountable for the accuracy of the work presented. MSB: generation of experimental data, its curation and interpretation, drafting of the manuscript, and final approval of the publication. MP: design of experimental plans, data interpretation, and final editing of the version to be published. CER: contributions to the concept, design of the work, and revising contents for final publication. SSD: writing/revising of content, data curation and interpretation, editing and final approval of the version to be published.
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The authors are shareholders of Novartis Pharmaceuticals Corporation (MSB, CER, SSD). No grants were awarded from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no competing interests.
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Bordawekar, M.S., Pudipeddi, M., Ruegger, C.E. et al. Formulation Intervention to Overcome Decreased Kinetic Solubility of a Low Tg Amorphous Drug. AAPS PharmSciTech 24, 149 (2023). https://doi.org/10.1208/s12249-023-02601-z
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DOI: https://doi.org/10.1208/s12249-023-02601-z