Recent Advances in Co-Former Screening and Formation Prediction of Multicomponent Solid Forms of Low Molecular Weight Drugs

Abstract

Multicomponent solid forms of low molecular weight drugs, such as co-crystals, salts, and co-amorphous systems, are a result of the combination of an active pharmaceutical ingredient (API) with a pharmaceutically acceptable co-former. These solid forms can enhance the physicochemical and pharmacokinetic properties of APIs, making them increasingly interesting and important in recent decades. Nevertheless, predicting the formation of API multicomponent solid forms in the early stages of formulation development can be challenging, as it often requires significant time and resources. To address this, empirical and computational methods have been developed to help screen for potential co-formers more efficiently and accurately, thus reducing the number of laboratory experiments needed. This review provides a comprehensive overview of current screening and prediction methods for the formation of API multicomponent solid forms, covering both crystalline states (co-crystals and salts) and amorphous forms (co-amorphous). Furthermore, it discusses recent advances and emerging trends in prediction methods, with a particular focus on artificial intelligence.

Keywords: co-amorphous; co-crystal; co-former screening; formation prediction of multi-component solid forms.

Figure 1

Representation of the different API solid-state forms.

Figure 2

Timeline of the development of co-former screening and formation prediction of multicomponent solid forms.

Figure 3

Relationship between the relative occurrence of co-crystals (AB neutral (grey)) and salts (A⁻B⁺ ionic (orange)) and the calculated ΔpK_a. Reprinted with permission from ref. [71]. Copyright 2012 Royal Society of Chemistry.

Figure 4

Different types of supramolecular synthons.

Figure 5

Four different synthons present in nicotinamide (a) and isonicotinamide (b) co-crystals with 3,5-pyrazole dicarboxylic acid. Reprinted with permission from ref. [32]. Copyright 2011 American Chemical Society.

Figure 6

MEPs representation displaying charge distribution (red for charge concentration and blue for charge depletion). Reprinted with permission from ref. [87]. Copyright 2022 Royal Society of Chemistry.

Figure 7

HBP approach for screening of multicomponent crystal forms.

Figure 8

HBP calculation for the system lenalidomide and nicotinamide. Reprinted with permission from ref. [42]. Copyright 2021 Elsevier.

Figure 9

Co-formers of indomethacin (top) and paracetamol (bottom) co-crystals. Successful and failed cases are highlighted in green and red, respectively. Reprinted with permission from ref. [102]. Copyright 2020 American Chemical Society.

Figure 10

Three unequal dimensions of a model box.

Figure 11

Multicomponent crystal forms screening of 2,4-dichlorophenoxyacetic acid based on COSMO-RS and MC methods. Reprinted with permission from ref. [106]. Copyright 2022 Royal Society of Chemistry.

Figure 12

Hansen spheroid with Ra indicating the distance between HSP₁ and HSP₂. Reprinted with permission from ref. [120]. Copyright 2022 Elsevier.

Figure 13

Relationship of H_mix between caffeine and theophylline. Reprinted with permission from ref. [52]. Copyright 2017 American Chemical Society.

Figure 14

Commonly used ML algorithms.

Figure 15

Screening framework of co-crystals. Reprinted with permission from ref. [130]. Copyright 2021 Springer Nature.

Figure 16

Steps for screening the formation of co-crystals based on the solubility of the pure components. Reprinted with permission from ref. [137]. *: at constant temperature. Copyright 2009 American Chemical Society.