Category: Formulation and Quality
Purpose: A challenge in pharmaceutical manufacturing is poor aqueous solubility of the active pharmaceutical ingredient (API). Cocrystals have recently been presented as an attractive approach to address these material limitations, and have been used to improve properties like tabletability, solubility, dissolution, and bioavailability. These physical improvements, however, are not guaranteed to be commensurate, i.e. increasing the aqueous solubility may subsequently reduce tabletability. This work tests the hypothesis that cocrystallization can be used to simultaneously improve the tabletability and aqueous solubility of a model API, theophylline (THY).
Methods: New cocrystals of theophylline (THY) with 3-nitrobenzoic acid (THY: 3-NBA) and 4-nitrobenzoic acid (THY: 4-NBA) were prepared by adding equal moles of THY and 3-NBA or THY and 4-NBA into a grinding jar that contained two grinding balls and a small amount of methanol to facilitate cocrystal formation through liquid assisted grinding (LAG). The powders were milled for 1.5 hours using a FTS vibratory mill at 1200 rpm, and the obtained product was dried at 70 °C for 24 hours. PXRD (powder X-ray diffraction) was performed on the materials using a Siemens D8 diffractometer to confirm cocrystal formation. P-BLS (powder Brillouin light scattering) spectra were collected for all materials using our custom-made p-BLS spectrometer operating at a laser wavelength of 532 nm, and mirror spacings of 3.0 mm and 7.0 mm. Characteristic frequencies from the p-BLS spectra were identified and used to calculate the aggregate mechanical moduli for all materials. Tableting studies on the individual coformers and cocrystals were performed at different compaction pressures (25-250 MPa) using a Carver Press (Model C, Wabash). A stainless-steel punch and die assembly (Natoli, Inc) was utilized to prepare 8 mm diameter, flat-faced tablets. Tensile strength of the compacts was measured using a Universal Stress Strain analyzer (QTestII, MTS Systems Corporation). Equilibrium aqueous solubilities of THY and its cocrystals were measured using UV-Vis spectroscopy. An excess amount of powder was added in 5ml water and left on an orbital shaker (60 rpm) for 72 hours at room temperature. The solutions were filtered (0.2 µm syringe filter) and analyzed using a Agilent 8543 UV-visible spectrophotometer.
Results: Powders obtained from the LAG process were found to be new materials, THY: 3-NBA and THY: 4-NBA. The PXRD patterns of both THY: 3-NBA and THY: 4-NBA displayed entirely new peaks, distinct from PXRD patterns of the original co-formers, confirming cocrystal formation. Mechanical moduli determined from the p-BLS spectra revealed that the Young’s modulus for THY (E = 9.6 GPa) modestly increased to 9.8 GPa for THY:3-NBA and 10.6 GPa for THY:4-NBA. The shear moduli followed a similar trend with THY being the lowest value (G = 3.8 GPa) and each co-crystal slightly increased with THY:3-NBA (G = 3.9 GPa) and THY:4-NBA (G = 4.1 GPa). These modest changes in material mechanics were corroborated by follow-on tabletability studies. Compressibility plots determined for all powders indicated a slight decrease in cocrystal compressibility (relative to THY) consistent with the rank-order of Young’s moduli observed. Tabletability profiles also revealed an improved tabletability of THY:3-NBA relative to THY at lower compaction pressures. Heckel analysis revealed that the yield pressures (Yp) were consistent across the material series: 152.1 MPa (THY), 160.5 MPa (THY:3-NBA) and 157.2 MPa (THY: 4-NBA). Results from our solubility studies revealed that THY has an equilibrium aqueous solubility of 7.8 mg/mL, which is consistent with the literature reported aqueous solubility. Upon cocrystallization, however, the aqueous solubility for THY: 3-NBA increased by over 40% to 11.1 mg/mL, but interestingly, a decrease in aqueous solubility of THY: 4-NBA with a value of 5.7 mg/mL was determined.
Conclusion: New 1:1 cocrystals of THY with 3-NBA and 4-NBA were obtained with liquid assisted grinding and confirmed using p-BLS and PXRD. Our p-BLS studies demonstrated that cocrystallization with either 3-NBA or 4-NBA did not significantly adjust the aggregate mechanical properties of THY. Moreover, the tabletability of our model API (theophylline) was not compromised by co-crystallization, but rather, for THY:3-NBA the compaction performance was improved, particularly at low pressures (P < 150 MPa). The aqueous solubility for THY: 3-NBA was further improved by over 40%, yet the THY:4-NBA cocrystal displayed a reduced solubility. Overall, the aqueous solubility of THY was significantly improved without any deterioration in mechanics or tableting performance. While cocrystals represent an attractive new avenue for engineering new materials, it is important to comprehensively evaluate the physico-chemical properties to ensure the new material is adequate for all aspects of manufacturing and use.