TY - JOUR
T1 - Role of lattice disorder in water-mediated dissociation of pharmaceutical cocrystal systems
AU - Kaur, Navpreet
AU - Duggirala, Naga Kiran
AU - Thakral, Seema
AU - Suryanarayanan, Raj
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/7
Y1 - 2019/7
N2 - Our objective is to mechanistically understand the implications of processing-induced lattice disorder on the stability of pharmaceutical cocrystals. Caffeine-oxalic acid (CAFOXA) and dicalcium phosphate anhydrate (DCPA) were the model cocrystal (drug) and excipient, respectively. Cocrystal-excipient mixtures were milled for short times (≤2 min) and stored at room temperature (RT)/75% RH. Milling-induced lattice disorder was quantified using powder X-ray diffractometry and gravimetric water sorption. Milling for even 10 s resulted in measurable disorder and an attendant tendency of the solid to sorb water. This was followed by cocrystal-excipient interaction leading to dissociation. The proposed mechanism of cocrystal dissociation entails the following sequence: sorption of water by disordered regions, dissolution of CAFOXA and DCPA in the sorbed water, followed by proton transfer from the coformer (oxalic acid) to DCPA, and the formation of hydrates of caffeine and calcium oxalate. As such, CAFOXA is a robust cocrystal, stable even under elevated humidity conditions (RT/98% RH). However, in a drug product environment, routine pharmaceutical processing steps such as milling and compaction have the potential to induce sufficient disorder to render it unstable.
AB - Our objective is to mechanistically understand the implications of processing-induced lattice disorder on the stability of pharmaceutical cocrystals. Caffeine-oxalic acid (CAFOXA) and dicalcium phosphate anhydrate (DCPA) were the model cocrystal (drug) and excipient, respectively. Cocrystal-excipient mixtures were milled for short times (≤2 min) and stored at room temperature (RT)/75% RH. Milling-induced lattice disorder was quantified using powder X-ray diffractometry and gravimetric water sorption. Milling for even 10 s resulted in measurable disorder and an attendant tendency of the solid to sorb water. This was followed by cocrystal-excipient interaction leading to dissociation. The proposed mechanism of cocrystal dissociation entails the following sequence: sorption of water by disordered regions, dissolution of CAFOXA and DCPA in the sorbed water, followed by proton transfer from the coformer (oxalic acid) to DCPA, and the formation of hydrates of caffeine and calcium oxalate. As such, CAFOXA is a robust cocrystal, stable even under elevated humidity conditions (RT/98% RH). However, in a drug product environment, routine pharmaceutical processing steps such as milling and compaction have the potential to induce sufficient disorder to render it unstable.
KW - Cocrystal
KW - Dissociation
KW - Lattice disorder
KW - Milling
KW - Processing
KW - Solid state stability
KW - Water
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U2 - 10.1021/acs.molpharmaceut.9b00386
DO - 10.1021/acs.molpharmaceut.9b00386
M3 - Article
C2 - 31117742
AN - SCOPUS:85069237012
SN - 1543-8384
VL - 16
SP - 3167
EP - 3177
JO - Molecular pharmaceutics
JF - Molecular pharmaceutics
IS - 7
ER -