Understanding solid-state processing of pharmaceutical cocrystals via milling: Role of tablet excipients

Discovery of novel cocrystal systems and improvement their physicochemical properties dominates the current literature on cocrystals yet required end-product formulation is rarely addressed. Drug product manufacturing includes complex API solid state processing steps such as milling, granulation, tableting. These all require high mechanical stress which can lead to solid-state phase transformations into polymorphs solvates, or dissociation individual components. Here we measured effect tablet excipients a range pharmaceutical formulations. Our findings were rationalised using Density Functional Theory (DFT) calculations intermolecular binding energies constituents co-milling excipients. A 1:1 stoichiometric ratio Theophylline (THP) co-former 4-Aminobenzoic acid (4ABA) was co-milled with five different excipients: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), lactose, microcrystalline cellulose (MCC). The experiments carried out in 10 25 ml milling jars at 30 Hz for times. Co-milled samples characterised formation transformation powder X-ray diffraction (PXRD) differential scanning calorimetry (DSC). data shows that presence PEG, HMPC lactose yields purer cocrystals, supported by calculated stronger excipient interactions PVP MCC. We identify suitably-prepared THP–4ABA stable under extended conditions.