Co-Crystallization Approach to Enhance the Stability of Moisture-Sensitive Drugs

Abstract

Stability is an essential quality attribute of any pharmaceutical formulation. Poor stability can change the color and physical appearance of a drug, directly impacting the patient's perception. Unstable drug products may also face loss of active pharmaceutical ingredients (APIs) and degradation, making the medicine ineffective and toxic. Moisture content is known to be the leading cause of the degradation of nearly 50% of medicinal products, leading to impurities in solid dose formulations. The polarity of the atoms in an API and the surface chemistry of API particles majorly influence the affinity towards water molecules. Moisture induces chemical reactions, including free water that has also been identified as an important factor in determining drug product stability. Among the various approaches, crystal engineering and specifically co-crystals, have a proven ability to increase the stability of moisture-sensitive APIs. Other approaches, such as changing the salt form, can lead to solubility issues, thus making the co-crystal approach more suited to enhancing hygroscopic stability. There are many reported studies where co-crystals have exhibited reduced hygroscopicity compared to pure API, thereby improving the product's stability. In this review, the authors focus on recent updates and trends in these studies related to improving the hygroscopic stability of compounds, discuss the reasons behind the enhanced stability, and briefly discuss the screening of co-formers for moisture-sensitive drugs.

Keywords: co-crystals; hygroscopicity; moisture-sensitive; stability.

Figure 1

Illustration of methods to improve the hygroscopic stability of moisture-sensitive APIs.

Figure 2

Trends of scientific publications from 2003 to 2022 for (A) Drug stability, hygroscopicity, (B) Co-crystals, drug stability, hygroscopicity. Data taken from Science Direct.

Figure 3

Schematics of the major surface structures of the ISO crystals and co-crystals. Pink dotted lines representing the major crystal faces are shown to indicate the faces that were horizontal and perpendicular to the paper sheet. The crystal face structures are shown with the stick models. Reprinted with permission from [8].

Figure 4

(A) Berberine chloride tetrahydrate (#1306671), (B) Berberine chloride-citric acid co-crystal (#1857453), (C) Berberine chloride-2emodin-ethanol co-crystal (#1862517), (D) Palmatine saccharinate salt (#1977091)), (E) Palmatine sulfosalicyate salt (#2053643)), (F) Palmatine-gallic acid co-crystal (#2075058) (from Mercury 2022.2.0, Build 353591). #—CCDC Identifier number.

Figure 5

Schematic chart showing the chemical and physical instabilities caused due to moisture ingress in an API.

Figure 6

Variation of T_g of amylodextrin with moisture fraction. Experimental data representing the glass transition as determined from conventional DSC (♦) and the reversing heat flow of modulated DSC (▴). Reprinted with permission from [44].

Figure 7

(A) Flow rate (g/s) vs. relative humidity percentage (RH) of the different methacrylate copolymers using stainless-steel funnels of 20 mm (■), 15 mm (▴), 10 mm (•). and 5 mm (♦) holes. Error bars represent the standard deviation, (B) Correlation between crushing strength, compression speed, and moisture content for 400 mg ibuprofen tablets. Reprinted with permission from [49] and [55], respectively.

Figure 8

SEM pictures of theophylline: (a) Form III crystals (before transition), (b) Half way during transition, (c) Form II crystals (after transition). Reprinted (adapted) with permission from [62]. Copyright 2007, American Chemical Society.

Figure 9

Theophylline-malonic acid co-crystals of (A) Triclinic, and (B) Monoclinic form, showing the difference in the malonic acid orientation. Reprinted (adapted) with permission from [28]. Copyright 2021, American Chemical Society.

Figure 10

(A,C)—Hydrogen bonding and aromatic stacking, (B,D)—Void space present within the co-crystals. Reprinted (adapted) with permission from [28]. Copyright 2021, American Chemical Society.

Figure 11

Phenazopyridine-phthalimide co-crystal structure. (a) Side view of hydrogen bond linked chain, (b) Top view of scissor-like chain, and (c) 3D structure of co-crystal. Reprinted (adapted) with permission from [96]. Copyright 2012, American Chemical Society.