1. INTRODUCTION:

In the pharmaceutical industry, it is the poor biopharmaceutical properties rather than toxicity or lack of efficacy that are the main reasons why less than 1% of active pharmaceutical compounds eventually appear in the marketplace. Among these biopharmaceutical properties, solubility remains a key issue with drugs often discarded during commercial production due to their low solubility^1,2. Active pharmaceutical ingredients (API) with poor aqueous solubility and dissolution rate have become more prevalent, often leading to suboptimal exposure in toxicology and clinical studies.

Solubility and dissolution rates are key factors in determining the efficacy as well as activity of a drug. The improvement of physicochemical properties of lipophilic drug without altering the structure is a particular challenge for the successful development of pharmaceutical products³.

As the oral route has always been preferred over other routes of administration due to its convenience, non-invasiveness, and cost-effectiveness, thus it has become necessary that the drug should have some aqueous as well as some lipid solubility for better absorption through this route⁴.

Various methods have been designed for solubility enhancement of API such as salt formation, emulsification, solid dispersion. The crystal engineering approach offers an alternative and potential route for improving the bioavailability of poorly soluble crystalline API. Application of cocrystallization technique can result in a salt, solvate, or polymorph⁵. Crystalline forms are strongly preferred because they tend to be more stable, reproducible, and amenable to purification than other types of solid forms such as amorphous solids and solid solutions. The dissolution rate and intrinsic solubility of different crystal forms are variable and can strongly influence bioavailability. Stability regarding temperature and humidity is crucially dependent upon crystal packing⁶.

A cocrystal is a multi-component crystal in which all components are usually solid at room temperature in a stoichiometric ratio and it involves non-covalent interactions such as hydrogen bonds, Van Der Waals bonds, ionic bonds in a crystal lattice. Cocrystals incorporate pharmaceutically acceptable guest molecules into a crystal lattice along with the API. Cocrystals a concept of supramolecular chemistry that is gaining extensive interest of researchers from pharmaceutical, chemical sciences and drug regulatory agencies because physiochemical properties of API can be improved using this technique. Cocrystallization with pharmaceutically acceptable GRAS compounds improve physicochemical and powder properties of API^7,8.

The drug selected for study is posaconazole which exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and indicated for prophylaxis of invasive aspergillus and candida infections in patients followed by, cell death⁹. Posaconazole has poor oral bioavailability which is attributed to its poor aqueous solubility of <1μg/mL, low gastrointestinal dissolution, and absorption^10,11. Its large positive food effect and high solubility−pH dependence have resulted in low and erratic bioavailability (fraction absorbed <30%) in addition to daily doses of posaconazole (300−600mg) that are over 1000 times higher than what can be dissolved in a luminal volume of 250mL¹². Available oral formulations include a suspension and delayed-release tablet. As it has a broad and unique spectrum of activity, crystal forms of posaconazole can be formulated as suspensions or solid dosage forms with less variability as well as better solubility, dissolution, stability, and properties suitable for pharmaceutical processing. Generation of cocrystal of posaconazole with 4-aminobenzoic acid (4AMB) using supercritical CO₂ as an antisolvent in GAS (Gas antisolvent) with acetonitrile, and as a solvent in CSS (Cocrystallization with supercritical solvent) methods is reported¹³. The present work was aimed to design and develop novel co-crystals of posaconazole to enhance dissolution rate and further formulated as tablets for immediate release.

2. MATERIALS AND METHODS:

Posaconazole was obtained as a gift sample from Aurobindo Pharma, Hyderabad, Telangana, India. Glutaric acid, succinic acid, and tartaric acid were obtained from S.D Fine Chemical Ltd (Mumbai, India).Ethanol was purchased from Research-Lab Fine Chem Industries (Mumbai, India). All other chemicals were of analytical grade.

Selection of co-formers:

The coformers are selected on basis of ∆pKa values, where ∆pKa is the difference of pKa of drug and coformers. The generation of salt or cocrystal can be predicted from ∆pKa value. If ΔpKa<0, a cocrystal will almost always result, and when ΔpKa>3, the result will most likely be a salt. The ∆ pKa values of the posaconazole and glutaric acid, was calculated^14,15.

Formulation of posaconazole cocrystal:

Posaconazole cocrystal was generated with glutaric acid, using solvent drop grinding method. 84.18mg (1mmol) of posaconazole was triturated with 15.87mg (1mmol) of glutaric acid using 50μL of ethanol for 30min, generating 100% yield. The cocrystals were stored in a desiccator under vacuum in vials sealed with parafilm. The generation of new form was confirmed by melting point, FTIR, PXRD, and DSC^16,17.

Determination of melting point:

The melting points of the posaconazole and prepared cocrystal were determined by capillary method using melting point apparatus (Biotech India, Mumbai).

Fourier transform infrared spectroscopy studies (FTIR):

The possible interaction between posaconazole and glutaric acid was studied by IR spectroscopy. IR spectroscopy was conducted using a FTIR spectrophotometer (Shimadzu Corporation, Tokyo, Japan) and the spectrum was recorded in the wavelength region of 4000 - 400 cm−¹. The pellet was placed in the light path and the spectrum was recorded¹⁸.

Powder X-ray diffraction studies (PXRD):

The PXRD was undertaken to investigate the crystalline nature of posaconazole and cocrystal. The study was carried out using an X-ray diffractometer, Shimadzu module XRD 7000 (2θ=10-80ºC), scan speed= 2 deg/min, Cu radiations) using cu kα radiation. Cocrystal formation was inferred from the emergence of new peaks, change in the intensity of the peaks, and shifting of the peaks.

Differential scanning calorimetry studies (DSC):

Thermal analysis of posaconazole and cocrystal were recorded on a DSC (Sicco DSC calorimeter Japan Module 7020). Powder samples (5-10mg) were weighed into an aluminium pan under nitrogen flow (30mL/min) at a rateof 10ºC per min from 0 - 300ºC and analyzed, an empty aluminium pan was used as a reference¹⁹.

Physicochemical characterization of cocrystal:

Saturation solubility studies:

Excess of posaconazole and its cocrystal were dissolved in 10ml 0.1 N hydrochloric acid solution. The flasks were agitated in an orbital shaking incubator at room temperature (25ºC), 100rpm for 24h and were analyzed at 255nm¹⁹.

Estimation of drug content in cocrystal:

Drug content was determined by dissolving 10mg of cocrystal in 100ml of 0.1 N hydrochloric acid solution. From the above solution, 1ml was pipetted out and volume was made up to 10ml using 0.1N hydrochloric acid solution, which yields a sample of concentration 10 µg/mL. The samples were analyzed using UV spectrophotometer (UV-1800; Shimadzu, Tokyo, Japan) and absorbances were measured at 255nm. Estimation of posaconazole was done in posaconazole cocrystal.

Powder dissolution study:

Dissolution studies were carried out in triplicate for 120 mins in USP dissolution test apparatus II (Electrolab USP XXII, scientific). Posaconazole and cocrystal containing the drug equivalent to 100mg were taken and filled in hard gelatin empty capsules. Dissolution studies were carried out in 900ml of 0.1 N HCl solution, at 37± 0.5ºC and stirring speed of 50rpm was used. Samples were withdrawn at time intervals of 10, 20, 30, 40, 50, 60, 90 and 120 minutes. The samples were filtered through 0.45-μm filter and analyzed spectrophotometrically at 255nm using 0.1 N HCl solution as blank.

Preparation of fast dissolving tablets:

The cocrystal formulation was further formulated into fast disintegrating tablets using sodium starch glycolate, croscarmellose sodium and crospovidone as superdisintegerating agent. The components of the prepared tablet formulations are presented in Table1. The posaconazole (100mg/tablet) or its equivalent cocrystal was geometrically mixed with other additives before compression into tablets using rotary tablet machine (CIP machineries Pvt. Ltd, Ahmadabad) with 8 mm rounded punch. The compression force was adjusted to produce tablets having a hardness of 4-5kp ^20,21,22. Prepared tablets were kept in zip bags and stored in a desiccator for further studies.

Table 1: Composition of posaconazole-glutaric acid cocrystal tablet with different disintegrating agents

S. No.	Ingredients	F1 (mg)	F2 (mg)	F3 (mg)
1	Posaconazole-glutaric acid co-crystal	125	125	125
2	Sodium starch glycolate	40	-	-
3	Croscarmellose sodium	-	40	-
4	Crospovidone	-	-	40
5	Magnesium stearate	1.5	1.5	1.5
6	Aerosil	1.5	1.5	1.5
7	Talc	1	1	1
8	Micro crystalline cellulose	31	31	31

Characterization of posaconazole-cocrystal tablets:

Hardness test:

The test was conducted on 10 tablets that were randomly selected. The hardness of each tablet was determined using Monsanto hardness tester.

Disintegration test:

This test employed the tablet disintegration tester (TGR56, Electrolab, India) which was loaded with six tablets. The disintegration time was monitored both in 0.1N hydrochloric acid solution. The time taken for complete disintegration of each tablet was recorded.

Estimation of drug content in posaconazole-glutaric acid cocrystal tablet:

The procedure involved the random selection of 30 tablets, 10 of which were individually subjected to drug content determination. The tablets were crushed and powdered equivalent to 100mg of the drug was dispersed in methanol to solubilize the posaconazole with the aid of a bath sonicator. The clear supernatant was suitably diluted before quantification of the posaconazole using the UV. The samples were analyzed using UV spectrophotometer and absorbance was measured at 255nm.

Dissolution study of posaconazole - glutaric acid cocrystal tablets:

Dissolution studies were carried out in triplicate for 120 mins in USP dissolution test apparatus II (Electrolab USP XXII, scientific). Posaconazole-glutaric acid co-crystal tablet (F1 formulation) and pure drug tablet were taken and dissolution studies were performed using 0.1 N hydrochloric acid solution temperature was maintained at 37±0.5ºC. Further similarity factor (F2) were calculated to compare dissolution profiles^22,23,24,25.

3. RESULTS AND DISCUSSION:

Selection of conformer:

The pKa value of the posaconazole and glutaric acid are 4.6 and 5.22 respectively (Literature value).ΔpKa value was calculated and observed to be (0.62). For ΔpKa between 0 < ΔpKa < 3 the outcome can be either a salt or cocrystal or a complex with partial proton transfer²⁶. It is noted that the ΔpKa value of formed adduct was found between 0 to 3 which implies any form but is not definitive.

Determination of melting point:

M.P of the prepared cocrystal were determined up to four weeks and observed to be constant during this period. Posaconazole-glutaric acid cocrystal showed a remarkable lowering of melting point in the range of 115-120°C which is neither nearer to posaconazole (170 °C) nor the coformer (glutaric acid-97°C).

FTIR studies:

Solid samples of posaconazole, coformer and cocrystals of posaconazole were taken for FTIR studies. The overlaid spectra of posaconazole, cocrysta., and coformer is shown in Figure 1.

Figure 1: FTIR spectral comparison of posaconazole, posaconazole - glutaric acid cocrystal and glutaric acid

Principal absorption peaks of API were observed at 1685.79 cm^-1 (C=O), 2877.79 cm^-1 (-CH aliphatic), 2964.59 cm^-1, 1548.84 cm^-1 (C–H deformation in aromatic rings), 1510.26 cm^-1 (C=N), 3116.97 cm^-1 (OH), 3053.32 cm^-1 (=C-H stretching). In posaconazole - glutaric acid cocrystal, shift has been observed in OH band (3485.37 cm^-1) which indicates cocrystals formation²⁷.

Powder X-ray diffraction:

Cocrystal formation between two solid-phases can be predicted by overlay of diffraction pattern of prepared cocrystal along with API and coformer. Diffraction pattern of posaconazole (Figure 2) impies crystalline nature of posaconazole, having peaks at 19.63 ̊, 17.64 ̊, and 15.72 ̊. The 2θ value for 100% intensity of posaconazole-glutaric acid cocrystal was observed at 17.87 ̊ while glutaricacid showed max intensity peak at 24.91 ̊. Cocrystal showed sharp peaks at 17.87 ̊, 19.81 ̊, and 22.17 ̊ indicating shifting in drug peaks. Posaconazole-glutaric acid cocrystals showed the presence of new peaks, and change in peak intensities implying different crystal habits and formation of new crystal form^28,29.

Figure 2: Overlay of the PXRD pattern of posaconazole-glutaric acid cocrystal with individual components

Differential scanning calorimetry:

Posaconazole-glutaric acid co-crystals showed a peak at 121.65 °C (Figure 3). In posaconazole-glutaric acid, endothermic peaks were observed, which were neither near to the melting point of posaconazole (168.48 °C) nor the coformer there by confiming formation of new forms ³⁰.

Figure 3: Comparative DSC graphs of API and Cocrystal

Posaconazole Cocrystals solubility determination:

The solubility of the pure drug was found to be 0.0053 mg/mL while posaconazole-glutaric acid cocrystals showed 0.0082 mg/mL solubility in 0.1 N HCl. Solubility of co-crystals was increased (1.5 folds) with glutatric acidolds) with sodium odium acetate predicting different physicochemical behavior³¹.

Estimation of drug content in cocrystals:

The estimated drug content in posaconazole-glutaric acid cocrystals was reported to be 81%. Along with drug content, coformer content was calculated by the difference in solid weights. The proportion of posaconazole and glutaric acid was estimated and was agreeing with the molar ratio taken (1:1).

Evaluation studies of Fast-disintegrating tablets:

Hardness:

The hardness of the posaconazole cocrystal tablets was found to be higher than posaconazole tablets (4±0.89 kp) which indicates better compressibility of formed cocrystals ( Table 2).

Disintegration studies:

Disintegration time (Table 2) was found to be least for F1 formulation which consists of sodium starch glycolate as super disintegrate compared to F2 (Croscarmellose sodium), F3 (Crospovidone), posaconazole tablet (control tablet with the absence of cocrystal). Sodium starch glycolate is used in oral pharmaceuticals as a disintegrant in tablets, capsules and can be used in direct-compression and as dissolution enhancing agent.The posaconazole with modified properties was prepared with glutaric acid and further formulated as orodispersible tablets with the objective of faster disintegration and a greater dissolution rate. Based upon the disintegration time F1 (sodium starch glycolate) is selected for further characterization.

Table 2: Disintegration time for different formulation of posaconazole cocrystal tablet and pure posaconazole tablet

Name	F1 (SSG)	F2 (CCS)	F3 (CP)	Posaconazole tablet
Disintegration time (seconds)	8± 0.81	40±2.30	42±1.73	87±1.52
Hardness(kp)	4.85 ± 0.7	4.75 ±0.81	4.5±0.75	4 ± 0.89

Drug content:

Drug content for F1formulation (sodium starch glycolate) and posaconazole tablets hydrochloric was found to be 99.4% and 98.45% respectively satisfying pharmacopeial limits (85-115%).

Dissolution studies:

The dissolution-time profile of posaconazole tablet and posaconazole-glutaric acid cocrystal tablet (F1 formulation) in 0.1 N hydrochloric acid solution is shown in Figure 4. Posaconazole tablets showed 56.23% in 120 mins while posaconazole - glutaric acid cocrystal tablets showed 100 % in 120 mins. It has been found that the posaconazole - glutaric acid cocrystal tablet exhibited a better dissolution pattern compared with the dissolution pattern of the posaconazole tablet.Posaconazole-glutaric acid co-crystal tablet exhibited f₂ value of 16, indicating dissolution abilities of cocrystals tabletsare not similar to pure posaconazoletablet. The enhancement in dissolution rate was 7 fold greater for posaconazole-glutaricacid co-crystal, tablet within 10 min points. Such a higher dissolution can be explained as spring and parachute behavior ³². The t_40min is nearly 80% for co-crystal tablets, suggesting the pharmacopoeial requirements.

Figure 4: Dissolution-time profile of posaconazole tablet and posaconazole-glutaric acid cocrystal

4. CONCLUSIONS:

Co-crystallization, a paradigm of crystal engineering, consists of the collection of more than two disparate solid entities in a crystalline lattice via non-covalent interactions. Co-crystallization by solvent drop grinding method was adopted to alter the physicochemical properties of the posaconazole. The posaconazole-glutaric acid cocrystals were characterized by melting point determination, FTIR, PXRD, DSC studies. Further cocrystals were punched into fast dissolving tablets by different super disintegrating agents. The tablets with sodium starch glycolate as a super disintegrating agent showed minimum disintegration time. Dissolution study showed that posaconazole-cocrystal tablets have improved the dissolution rate of posaconazole significantly compared to posaconazole alone.Based on results it can be concluded that pharmaceutical co-crystallization is an effective approach for solid-state manipulation for possible improved physicochemical properties of posaconazole.

5. ACKNOWLEDGEMENTS:

The authors are thankful to NIPER Hyderabad for providing PXRD and DSC facility.

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Received on 01.03.2023 Modified on 07.07.2023

Research J. Pharm. and Tech 2024; 17(4):1771-1776.

DOI: 10.52711/0974-360X.2024.00281