Efficient Screening of Coformers for Active Pharmaceutical Ingredient Cocrystallization

Controlling the physical properties of solid forms for active pharmaceutical ingredients (APIs) through cocrystallization is an important part of drug product development. However, it is difficult to know a priori which coformers will form cocrystals with a given API, and the current state-of-the-art for cocrystal discovery involves an expensive, time-consuming, and, at the early stages of pharmaceutical development, API material-limited experimental screen. We propose a systematic, high-throughput computational approach primarily aimed at identifying API/coformer pairs that are unlikely to lead to experimentally observable cocrystals and can therefore be eliminated with only a brief experimental check, from any experimental investigation. On the basis of a well-established crystal structure prediction (CSP) methodology, the proposed approach derives its efficiency by not requiring any expensive quantum mechanical calculations beyond those already performed for the CSP investigation of the neat API itself. The approach and assumptions are tested through a computational investigation on 30 potential 1:1 multicomponent systems (cocrystals and solvate) involving 3 active pharmaceutical ingredients and 9 coformers and one solvent. This is complemented with a detailed experimental investigation of all 30 pairs, which led to the discovery of five new cocrystals (three API–coformer combinations, a polymorphic cocrystal example, and one with different stoichiometries) and a cis-aconitic acid polymorph. The computational approach indicates that, for some APIs, a significant proportion of all potential API/coformer pairs could be investigated with only a brief experimental check, thereby saving considerable experimental effort.


Computing quantity ΔΔUc
. The unit cell and space group symmetry are distinct from the already known structure of cis aconitic acid form I (Pbca, Z'=1). The molecular conformations present in the two cis aconitic acid polymorphs differ substantially. In form I one of the acid groups forms an intramolecular O−H···O hydrogen bonding interaction to a second carboxylic acid function (Figure 1.b). This is in contrast to form II, where all three of the carboxylic acid protons form intermolecular interactions. Five strong hydrogen bonding interactions are formed in form I, one carboxylic acid dimer [( 2 2 (8)] 1 , one 1 1 (7) chain and the intramolecular hydrogen bond. The second polymorph forms six hydrogen bonding interactions, two 2 2 (8) dimers one 1 1 (7) chain motif with all interactions being O−H···O (Figure 1.c). Furthermore, C−H···O close contacts stabilise the structure. Finally, the cis aconitic acid pure form investigation is slightly different. Experimental indications suggested that the intramolecular hydrogen bond may be broken, necessitating broadening the search ranges, as the initial investigation had assumed the intramolecular hydrogen bond was maintained.
An overview over the paracetamol crystallization experiments is given in Table S1 and selected PXRD diffractograms are shown in Figure S1 - Figure S10. n.a.
-not attempted, yes -cocrystal/solvate formation, x -physical mixture of the two compounds.

Carbamazepine (CARB) cocrystal screen
All experimental cocrystals (nicotinamide, oxalic acid, succinic acid) were reproduced in the experimental screen. Furthermore, new cocrystals were found with methyl parabene, t-butyl-4hydroxyanisole and cis-aconitic acid (Table S3, Figure S21 - Figure S29). In case of propyl paraben one experiment resulted in a new pattern.        Additional cocrystallization experiments were undertaken for the combination carbamazepine and propyl parabene (Table S4) with the aim to reproduce the phase seen in the initial n-heptane slurry experiments ( Figure S23). Therefore, the range of solvents, molar ratios and crystallisation techniques was extended. None of the additional experiments resulted in a cocrystal.
diisopropyl ether x n. a. n. a.
n-butanol x n. a. n. a.

n-heptane
x, x a n. a. n. a.  were considered complete when energies were converged to better than 2x10 −5 eV per atom, atomic displacements converged to 1x10 −3 Å, maximum forces to 5x10 −2 eV Å −1 , and maximum stresses were converged to 1x10 −1 GPa.

Carbamazepine: 3-t-butyl-4-hydroxyanisole BHA cocrystals (CARB:ESAL-A)
The fixed cell PBE-TS structure was used as the starting point for rigid body Rietveld refinements in TOPAS academic. 3 The final refinements included a total of 54 parameters (

Carbamazepine:methyl paraben CEBG cocrystals (CARB-CEBG-A)
The fixed cell PBE-TS structure was used as the starting point for rigid body Rietveld refinements in TOPAS academic. 3

cis Aconitic acid (form II)
The PBE-TS structure (fixed cell parameters) were used as the starting point for rigid body Rietveld refinements in TOPAS academic. 3 The final refinements included a total of 58 parameters (38 profile, 4 cell, 1 scale, 1 isotropic temperature factor, 3 position and 3 rotation, 8 preferred orientation) yielding a final Rwp= 8.02%. Note that only one position of the likely disordered COOH function was refined.