Investigation of the formation of drug-drug cocrystals and coamorphous systems of the antidiabetic drug gliclazide

Abstract

The antidiabetic drug gliclazide (GLZ) has a slow absorption rate and a low bioavailability due to its poor solubility. GLZ is often prescribed along with an antihypertensive, as many diabetic patients have coexistent hypertension. Cocrystallization and coamorphization are attractive strategies to enhance dissolution rates and to reduce the number of medications a patient has to take. In this work the formation of cocrystals and coamorphous systems of GLZ with various antihypertensive drugs was studied, namely chlorothiazide (CTZ), hydrochlorothiazide (HTZ), indapamide (IND), triamterene (TRI) and nifedipine (NIF) as well as benzamidine (BZA) as a model for the amidine pharmacophore. TRI, IND and HTZ were found to form coamorphous systems with GLZ that are stable for at least six months at 22  2 C and 56 % relative humidity. Coamorphous GLZ-TRI is also stable in dissolution medium. Coamorphization of GLZ-TRI with 15 % sodium taurocholate gave a viable coamorphous formulation with an enhanced dissolution rate. Comilling of GLZ with BZA and cocrystallization from solution gave the amorphous and crystalline salt, respectively and the X-ray structure is reported. During attempts to obtain X-ray suitable cocrystals crystals of 2 Na + GLZand IND . 0.5H2O were obtained. Redetermination of the published structure of IND . 0.5H2O revealed a unit cell with the length of the a axis doubled, a different space group and no disorder. Liquid-assisted grinding of a 1:1 mixture of GLZ and IND indicated the transformation of IND to a new solid-state form, while GLZ remained unaltered. Milling-and heating-induced solid-state transformations of IND are discussed.

Solubility Enhancement of Antidiabetic Drugs Using a Co‐Crystallization Approach

“…Aljohani and co‐workers [38] attempted to co‐crystallize GLZ with antihypertensive drugs chlorothiazide (CTZ), hydrochlorothiazide (HCTZ), indapamide (IND), triamterene (TRI) and nifedipine (NIF). These antihypertensive drugs are also BCS class II.…”

Synthesis, Characterization, and Intrinsic Dissolution Studies of Drug–Drug Eutectic Solid Forms of Metformin Hydrochloride and Thiazide Diuretics

“…For this system, using intrinsic dissolution rate (IDR) experiments, it was found that the % release of HTZ in DDES HTZ-atelonol (0.3:0.7) compared with pure HTZ has a 10-fold improvement. Analogously, Pharmaceutics 2021, 13,1926 3 of 21 the formation of the coamorphous systems glicazide-HTZ and glicazide-CTZ have been reported, seeking to improve the dissolution properties of the thiazide drugs [57], however, with no noticeable difference between the dissolution rates of amorphous/crystalline HTZ and the release rate of HTZ from the coamorphous glicazide-HTZ [57]. However, similar IDR experiments showed that the coamorphous form HTZ-atelonol (0.5:0.5~1:1) has a K int 12.5-fold more than HTZ crystalline and 2.2-fold better than the PM HTZ-atelonol [58].…”

“…Taking this into account, we are interested in the preparation of drug-drug solid forms containing MET•HCl (classified as class III, exhibiting high solubility in water but low permeability to cell membranes) [59], in the presence of the thiazide diuretics HTZ or CTZ (Scheme 1), in order to tackle the poor solubility and limited dissolution properties of both drugs, and because many T2D patients medicated with antidiabetic drugs frequently present hypertensive complications. Thus, this paper reports the ball-milling synthesis, using neat grinding (NG) [60][61][62][63][64] or liquid-assisted grinding (LAG) [60][61][62][63][64] (varying the polarity of the solvent), and characterization [57], as well as IDR experiments to determine any modification in the dissolution properties of these solid forms compared with the pure APIs. At first, we thought we had prepared DDCs, however during characterization we discovered the formation of DDESs.…”

Enhancement of Dissolution Rate and Bioavailability of Nifedipine by Chitosan Based Cocrystallization Technique

“…There are various practical approaches to improve the solubility of these include the use of particle size manipulation via micronization and nanonization, use of complexing agents such as cyclodextrins. The preparation of high energy drug states related to polymorphic or amorphic transformations use of co-solvents, micellar solutions and lipid based systems for lipophilic drugs are also one of the techniques to improve the solubility behaviour [8,9].…”