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 : 2025-03-03 Epub Date: 2025-02-12 DOI:10.1021/acs.molpharmaceut.4c01481

Chaowang Zeng, Jinghan Li, Jiawanjun Shi, Simon Bates, Bhushan Munjal, 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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调节甘露醇在冷冻溶液中结晶的物理形态：溶质和加工的作用。

甘露醇被广泛用作冻干制剂中的填充剂。我们的目的是评估非结晶性co溶质在抑制甘露醇结晶和防止在冷冻溶液中形成甘露醇半水合物（MHH）中的作用。采用差示扫描量热法（DSC）和x射线衍射法（XRD）研究了两种常用稳定剂（蔗糖和海藻糖）和三种模式蛋白（溶菌酶、牛血清白蛋白和免疫球蛋白G）对甘露醇结晶行为的影响。糖比蛋白质具有更明显的结晶抑制作用。在糖的存在下，甘露醇主要结晶为MHH，而蛋白质促进了δ-甘露醇的结晶。将冷冻溶液在-25℃下退火有利于MHH结晶。-10℃的较高退火温度加速了甘露醇的结晶，促进了无水δ-多晶的形成。退火可以克服蛋白质的结晶抑制作用，而在高糖浓度下，即使退火，仍有相当一部分甘露醇保持无定形。

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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.