Clotrimazole–cyclodextrin based approach for the management and treatment of Candidiasis – A formulation and chemistry-based evaluation

Abstract

Clotrimazole (CT) is a poorly soluble antifungal drug that is most commonly employed as a topical treatment in the management of vaginal candidiasis (VCD). The present work focuses on a formulation approach to enhance the solubility of CT using cyclodextrin (CD) complexation. A CT-CD complex was prepared by a co-precipitation method. Various characterization techniques such as differential scanning calorimetry (DSC), infrared (IR) and X-ray spectroscopy, scanning electron microscopy and nuclear magnetic resonance (NMR) spectroscopy were performed to evaluate the complex formation and to understand the stereochemistry between CT and CD. Computational molecular modeling was performed using the Schrödinger suite and Gaussian 09 program to understand structural conformations of the complex. The phase solubility curve followed an AL-type curve, indicating formation of a 1:1 complex. Molecular docking studies supported the data obtained through NMR and IR studies. Enthalpy changes confirmed that complexation was an exothermic and enthalpically favorable phenomenon. The CT-CD complexes were formulated in a gel and evaluated for release and antifungal activity. The in-vitro release studies performed using gels demonstrated a sustained release of CT from the CT-CD complex with the complex exhibiting improved release relative to the un-complexed CT. Complexed CT-CD exhibited better fungistatic activity towards different Candida species than un-complexed CT

Solubility and Thermodynamic Properties of Clotrimazole in 16 Organic Solvents at Temperature of 283.15 to 323.15 K

“…The melting point ( T m ) is 416.40 K, and the melting enthalpy (Δ fus H ) is 33.04 kJ/mol. These values are consistent with those reported in refs , , as shown in Table . Based on these values, the relative standard deviations of T m and Δ fus H are calculated to be 0.10% and 1.85%, respectively.…”

Enhanced Solubility and Bioavailability of Clotrimazole in Aqueous Solutions with Hydrophobized Hyperbranched Polyglycidol for Improved Antifungal Activity

“…The comparison of the FTIR spectrum of CLT obtained after subtraction of the spectrum of methanol from the spectrum of CLT loaded in the dry BPh40 carrier shows very good agreement, and only the shifts are observed within the bands located around 750, 920, and 1200 cm –1 . These lines may be assigned to the stretching of C–Cl groups (750 cm –1 ) 7 and C–H and C–N groups in the imidazole ring (917 and 1206 cm –1 , respectively). 27 These lines are sensitive to interactions with the environment.…”

“…3−6 In the therapy of vulvovaginal candidiasis, clotrimazole (CLT), i.e., an imidazole derivative belonging to the azole class of antifungal compounds, is commonly used in the form of creams, ointments, globules, and tablets. 7 It shows mainly the activity against C. albicans, along with very low anti-C. glabrata activity. 5,8 The bioavailability of CLT is limited in the aqueous medium due to its low solubility in water (0.49 μg/mL) 9 in consequence, therapeutic efficiency is reduced.…”

“…In the therapy of vulvovaginal candidiasis, clotrimazole (CLT), i.e. , an imidazole derivative belonging to the azole class of antifungal compounds, is commonly used in the form of creams, ointments, globules, and tablets . It shows mainly the activity against C.…”

“…glabrata activity. , The bioavailability of CLT is limited in the aqueous medium due to its low solubility in water (0.49 μg/mL) and, in consequence, therapeutic efficiency is reduced. Furthermore, in the case of intravaginal therapy, frequent administration of globules or tablets is required as the content of the therapeutic formulation is often released uncontrollably. , In fact, the affected site is often not adequately penetrated by the bioactive compound, its absorbed amount is below the therapeutic dose, leading to recurrent candidiasis and ultimately may be the cause of infertility . For this reason, the number of azole-resistant fungal infections is still increasing. − …”