Mechanochemical Co-crystallization of Clotrimazole and Development of an Optimized Vaginal Tablet

Vulvovaginal candidiasis (VVC) is a common infection associated with discomfort and reduced quality of life. Local therapy via vaginal dosage forms is preferred because drug is delivered directly to the site of infection, systemic exposure is reduced, and effective local concentrations can be achieved. Among available dosage forms, vaginal tablets are convenient, stable, easy to handle, and can be manufactured by scalable processes such as direct compression—making them suitable for routine therapy as well as large-scale supply. [2,3]

Clotrimazole is a widely used azole antifungal, but its performance is limited by poor aqueous solubility. According to the Biopharmaceutic Classification System, clotrimazole is commonly discussed as a class II drug (high permeability, low solubility), making dissolution a key step for local availability. [9] When solubility is low, dissolution can be slow, which may delay therapeutic levels at the vaginal mucosa. Conventional solubility enhancement methods exist, but they can add formulation complexity or introduce stability challenges. A solid-state approach that improves solubility without changing the drug’s chemical identity is therefore valuable for developing robust vaginal tablets.

Pharmaceutical co-crystallisation is one such approach. Regulatory guidance describes co-crystals as crystalline materials composed of two or more different molecules (typically an API and a co-former) in the same crystal lattice. [4] Co-crystals can modify melting behaviour, solubility, dissolution rate, and processing attributes while keeping the API chemically intact. [5–7] In this work, multiple GRAS co-formers were screened to prepare co-crystals of Clotrimazole; the optimised system was characterised using solid-state techniques (FTIR/DSC/PXRD); and the selected co-crystal was formulated into vaginal tablets and evaluated for tablet quality and dissolution performance in simulated vaginal fluid (pH 4.5).

MATERIALS AND METHODS

Materials

Clotrimazole was used as the active pharmaceutical ingredient (API). The following co-formers were screened for co-crystal formation: tartaric acid, cinnamic acid, ascorbic acid, maleic acid, m?toluic acid, and thiourea. Simulated vaginal fluid (SVF) of pH 4.5 was used as dissolution medium for in?vitro release testing; the SVF concept is based on established vaginal fluid simulant literature. [8]

Co-crystal preparation by liquid-assisted grinding (LAG)

Drug and co-former were weighed in the desired molar ratio and triturated using mortar and pestle. A minimal quantity of volatile solvent (few drops) was added to promote co-crystallisation under mechanochemical conditions. Initial screening was carried out at 1:1 molar ratio. Promising systems were further evaluated at 1:2 and 1:3 ratios. [6,7]

Evaluation of co-crystals

Prepared co-crystals were evaluated for melting point, saturated solubility (UV quantification), and morphology (microscopy). The optimised co-crystal was further characterised by FTIR, DSC, and PXRD to support formation of a distinct solid phase. [6]

Vaginal tablet formulation (direct compression)

The selected co-crystal was formulated into vaginal tablets by direct compression. Powder blend was mixed, lubricated, and compressed using rotary tablet compression with B?tooling.

Table 1. Composition of vaginal tablet (per tablet)

Dissolution study

Dissolution testing was performed in SVF (pH 4.5) using USP type II (paddle) apparatus. Medium volume: 100 mL; paddle speed: 50 rpm; temperature: 39 ± 0.5 °C (bath) and 37 ± 0.5 °C (bowl). Samples were withdrawn at 5, 10, 15, 20, 30, 45, 60, and 75 minutes and analysed at 263 nm.

RESULTS AND DISCUSSION

Co-crystal screening: melting point shift

Co-crystals prepared at 1:1 ratio exhibited melting points distinct from the pure drug and co-formers (Table 2), suggesting alteration of the solid-state arrangement and potential new phase generation.

Table 2. Melting points of screened co-crystals (1:1, LAG)

Saturated solubility screening and co-former selection

Saturated solubility screening at 1:1 ratio (Table 3) identified clotrimazole–ascorbic acid (CLT–AA) as the best-performing system, followed by CLT–cinnamic acid. Figure 1 visualises the comparative solubility across screened co-formers.

Table 3. Saturated solubility screening (1:1, LAG)

Figure 1. Saturated solubility screening of clotrimazole co-crystals (1:1, LAG).

Stoichiometric optimisation

Promising co-crystals (CLT–AA and CLT–cinnamic acid) were evaluated across multiple drug:co-former ratios. The CLT–AA 1:2 system provided the highest solubility among tested ratios (Table 4), supporting selection of 1:2 as the optimised ratio. Figure 2 summarises the effect of stoichiometry on saturated solubility.

Table 4. Effect of stoichiometric ratio on saturated solubility

Figure 2. Effect of drug:co-former ratio on co-crystal solubility.

Solid-state characterisation of the optimised co-crystal

The optimised CLT–AA (1:2) co-crystal was characterised using FTIR, DSC, and PXRD. Shifts/changes in characteristic FTIR bands, distinct thermal transition(s) in DSC, and emergence of new PXRD peaks along with disappearance/attenuation of parent peaks support formation of a distinct crystalline phase. [6]

Micromeritics and assay

Micromeritic parameters (Table 5) and drug content (Table 6) were evaluated to support processability and confirm drug loading.

Table 5. Micromeritics properties

Table 6. Drug content (assay)

Tablet evaluation

Vaginal tablets containing the optimised co-crystal were evaluated for key physical parameters (Table 7). All measurements were within acceptable limits for a directly compressed vaginal tablet.

Table 7. Physical evaluation of vaginal tablets

In?vitro dissolution in SVF (pH 4.5)

Dissolution testing in simulated vaginal fluid (SVF, pH 4.5) demonstrated that the CLT–AA (1:2) co-crystal achieved substantially higher cumulative release than pure clotrimazole and also exceeded marketed preparation at most time points (Table 8, Figure 3). [8]

Table 8. % cumulative drug release (%CDR) in SVF (pH 4.5)

Figure 3. Dissolution profile in simulated vaginal fluid (SVF) of  pH 4.