Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal

Abstract

A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D0D to 0.29 for D0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.

Structural, Physicochemical, and Biopharmaceutical Properties of Cocrystals with RS- and R-Praziquantel─Generation and Prolongation of the Supersaturation State in the Presence of Cellulosic Polymers

“…Dissolution studies for R-PZQ embedded in the cocrystalline phase with L-MA revealed an improved intrinsic dissolution rate constant compared to R-PZQ•0.5H 2 O (6.1-fold increase) and RS-PZQ (12.5-fold increase). 40 In continuation of our ongoing research interest on cocrystalline phases with low-soluble APIs, 24,39,40,45,46 we report herein on two novel cocrystals containing only the biologically active enantiomer R-PZQ, i.e., R-PZQ/SA and R-PZQ/GA (where SA = succinic acid and GA = glutaric acid). The novel phases were characterized by standard techniques (infrared (IR) spectroscopic, thermogravimetry-differential scanning calorimetry (TG-DSC), powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction (SCXRD) analysis) and basic biopharmaceutical tests (intrinsic dissolution rate and powder dissolution measurements in the presence and absence of cellulosic polymers), and compared with the analogous phases of RS-PZQ, viz., RS-PZQ/SA and RS-PZQ/GA.…”

“…In consequence, cocrystals exhibiting a solubility advantage and supersaturation behavior have the potential to enhance in vivo drug absorption but pose also a risk if uncontrolled supersaturation is leading to rapid (or even instantaneous) precipitation or if solid phase transformation is occurring. , An option to conserve the supersaturation state of low-soluble APIs over a prolonged time period and to protect solids from phase transformation consists in the addition of a polymer, solubilizing agent and/or a surfactant. ,− In vivo models have shown that such approaches can increase the absorption of the API. , …”

“…In continuation of our ongoing research interest on cocrystalline phases with low-soluble APIs, ,,,, we report herein on two novel cocrystals containing only the biologically active enantiomer R- PZQ, i.e ., R- PZQ/SA and R- PZQ/GA (where SA = succinic acid and GA = glutaric acid). The novel phases were characterized by standard techniques (infrared (IR) spectroscopic, thermogravimetry-differential scanning calorimetry (TG-DSC), powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction (SCXRD) analysis) and basic biopharmaceutical tests (intrinsic dissolution rate and powder dissolution measurements in the presence and absence of cellulosic polymers), and compared with the analogous phases of RS- PZQ, viz ., RS- PZQ/SA and RS- PZQ/GA. , Compared to RS -PZQ, RS -PZQ·0.5H 2 O and R -PZQ·0.5H 2 O, cocrystals R- PZQ/SA and R- PZQ/GA generate a solubility advantage and show increased intrinsic dissolution rates in aqueous medium simulating gastric fluid (HCl, pH 1.2), highlighting the importance of studying cocrystalline forms of enantiomerically pure APIs with limited solubility, especially in cases, in which an efficient deracemization method for conversion to the biologically active enantiomer is feasible …”

New Cocrystallization Method: Non-photochemical Laser-Induced Nucleation of a Cocrystal of Caffeine–Gallic Acid in Water

“…In some cases, CAF is used in a drug-drug cocrystal such as with saccharin, 61 quercetin, 62 eosin, 53 theophylline, 63 sulfacetamide, 64 furosemide, 65 genistein, 66 myricetin, 67 dihydromyricetin, 68 4-aminosalicylic acid, 69 baicalein, 70 epalrestat, 71 indomethacin, 72 paracetamol, 73 zonisamide, 74 dapsone, 75 5-fluorocytosine, 76 luteolin, 77 naringenin, 78 fisetin, 79 famotidine, 80 hydrochlorothiazide, 81 apixaban, 82 pyrimethamine, 83 niflumic acid, 84 and chlorthalidone. 85 The criteria to select the coformer for an NPLIN experiment could be described as follows: a molecule i) that has a great facility to crystallize attested by many structures reported; ii) that its solubility is close to that of CAF in the given solvent; iii) that does not absorb at 532 nm. Among them, gallic acid (GAL) has been chosen, in this NPLIN study.…”

“…Among them, one can mention oxalic acid, malonic acid, maleic acid, glutaric acid, formic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, 2-, 3-, 4-hydroxybenzoic- and 2,3-, 2,4-, 2,5-, 3,4-, and 3,5-dihydroxybenzoic acid, gallic acid, − 2-hydroxy-1-naphthoic acid, p -coumaric acid, 4-hydroxybenzoic acid, benzoic acid, p -formylphenoxyacetic acid, 1- and 2-naphthoxyacetic acid, dipicolinic acid, 4-chloro-3-nitrobenzoic acid, cinnamic acid, mesaconic acid, dimethylsuccinic acid, L-malic acid, anthranilic acid, 5-aminoisophthalic acid, 3-nitrobenzoic acid, tannic acid, glycolic acid, trimesic acid, isophthalic acid, benzene-1,3,5-tricarboxylic, and benzene-1,2,3-tricarboxylic acid . In some cases, CAF is used in a drug–drug cocrystal such as with saccharin, quercetin, eosin, theophylline, sulfacetamide, furosemide, genistein, myricetin, dihydromyricetin, 4-aminosalicylic acid, baicalein, epalrestat, indomethacin, paracetamol, zonisamide, dapsone, 5-fluorocytosine, luteolin, naringenin, fisetin, famotidine, hydrochlorothiazide, apixaban, pyrimethamine, niflumic acid, and chlorthalidone …”