Role of polymers in solution and tablet-based carbamazepine cocrystal formulations

Abstract

The aim of this study was to evaluate the influence of three chemically diverse polymers of Hydroxypropylemthylcellulose acetate succinate (HPMCAS), Polyvinylpyrrolidone (PVP) and PolyEthylene Glycol (PEG) on the phase transformation of three carbamazepine (CBZ) cocrystals of carbamazepine-nicotinamide (CBZ-NIC), carbamazepine-saccharin (CBZ-SAC) and carbamazepine-cinnamic acid (CBZ-CIN) in solution and tablet based formulations. Ba sed on the solubility and powder dissolution studies, it demonstrates that cocrystals can be easily formulated through a simple solution formulation or powder formulation to generate supersaturated concentrations and faster dissolution rates to overcome th ose drugs with solubility and/or dissolution limited bioavailability. However, a polymer based CBZ cocrystal tablet formulation has not shown any advantage of an improved CBZ release rate compared with the formulation of CBZ III or physical mixtures of CBZ III and coformers. This is contradictive to the solution behaviours of CBZ cocrystals in the solubility and powder dissolution tests because crystallization of the stable solid form of CBZ dihydrate (CBZ DH) within the tablet has taken place, leading to a reduced drug release rate and incomplete release. The mechanism of a polymer inhibition effect on the drug precipitation in solution has been elucidated through investigating the molecular interactions among CBZ, coformers and polymers in solution using infrared spectroscopy. Finally the formulation strategy has been proposed to capture the significant advantage of cocrystals.

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

“…Indeed, rapid conversion of the cocrystals into pure drug was demonstrated by PXRD analysis of the solids recovered after the dissolution tests in short time periods (~1-5 min, Figure 3). A similar behavior has been documented for other cocrystal phases in the literature [24,25,30,36,37,[55][56][57]. For example, exemestane-maleic-acid cocrystals did not increase solubilization of the drug due to rapid phase transformation [55].…”

“…The dissolution performance of the formulated solid samples was analyzed by means of powder dissolution tests using the USP 1 (basket) apparatus. A similar strategy was employed for the evaluation of formulated cocrystals of carbamazepine [29,30]. The dissolution profiles in pH 7.5 PBS for NTZ in pure form, a 2:1 stoichiometric physical mixture of NTZ and SUC, and NTZ-SUC (2:1) cocrystals formulated with an increasing amount of Methocel ® 60 HG are given in Figure 6.…”

“…Cellulosic polymers are the most common hydrophilic polymers used for the development of formulations with cocrystals [24,26,28,29,33,36,37]. They can inhibit or at least delay phase transformations of cocrystals [29,30], by establishing drug-polymer interactions [37] and maintaining the solubilization state of APIs. Therefore, the improvement of the NTZ dissolution profiles in the presence of pre-dissolved polymer could be explained by the following mechanism: after the rapid NTZ release into solution starting from the cocrystal, the cellulosic polymer interacts with NTZ molecules delaying its nucleation and eventually NTZ crystallized also interact with polymer interfering the crystal growth and agglomeration process.…”

“…In this line, there are several recent reports on the effect of polymers and surfactants in increasing solubility and dissolution rates of poorly soluble drugs, starting from a cocrystalline solid phase. Some representative APIs and nutraceutical compounds studied under this approach are celecoxib [23], danazol [24], indomethacin [25], carbamazepine [26][27][28][29][30][31], flufenamic acid [32], cilostazol [33], resveratrol [34], dihydromyricetin [35], tadalafil [36], exemestane [37] and posaconazole [38].…”

Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution

“…5,6 In order to maximise the potential of cocrystals, it is critical to include inhibitors in a formulation to prevent or delay the precipitation of the parent drug during dissolution. [7][8][9][10][11][12][13] Although polymeric crystallization inhibitors have been extensively studied in many other systems, in particular amorphous solid dispersions, 14,15 such studies are still rare for cocrystal based formulations. In a recent study, we have found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining the supersaturation through nucleation inhibition and crystal growth modification in a supersaturated cocrystal solution with a pre-dissolved polymer.…”