Modulating the Physical Form of Mannitol Crystallizing in Frozen Solutions: The Role of Cosolute and Processing

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Pharmaceutics Pub Date : 2025-02-12 DOI:10.1021/acs.molpharmaceut.4c0148110.1021/acs.molpharmaceut.4c01481

Chaowang Zeng, Jinghan Li, Jiawanjun Shi, Simon Bates, Bhushan Munjal and Raj Suryanarayanan*,

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Abstract

Mannitol is widely employed as a bulking agent in lyophilized formulations. Our goal was to evaluate the role of noncrystallizing cosolutes in inhibiting mannitol crystallization and preventing the formation of mannitol hemihydrate (MHH) in frozen solutions. The individual influence of two common stabilizers (sucrose and trehalose) and three model proteins (lysozyme, bovine serum albumin, and immunoglobulin G) on the crystallization behavior of mannitol was investigated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Sugars exerted a more pronounced crystallization inhibitory effect than proteins. In the presence of sugars, mannitol predominantly crystallized as MHH while the proteins facilitated the crystallization of δ-mannitol. Annealing the frozen solutions at −25 °C favored MHH crystallization. A higher annealing temperature of −10 °C accelerated mannitol crystallization and promoted the formation of the anhydrous δ-polymorph. The crystallization inhibitory effect of proteins was surmounted with annealing, while at a high sugar concentration, a substantial fraction of mannitol was retained amorphous even after annealing.

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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.