Introduction  

Pharmaceutical cocrystals have emerged recently as a promising approach to solve an essential challenge in the pharmaceutical industry, which is the delivery of active pharmaceutical ingredients (APIs) that possess limited aqueous solubility and inadequate bioavailability [1-4]. Cocrystals are often described as crystals that consist of two or more neutral components that are solids under ambient conditions. The two compounds, mainly API and a coformer, are connected through hydrogen bonding between the complementary functional groups. The bonding enable them to form supramolecular synthon, like carboxylic acid ......carboxylic acid, carboxylic acid……amide, carboxylic acid......aromatic nitrogen, and amide…...amide [5, 6]. It has been reported that cocrystals have a profound capacity to modulate the physicochemical properties of drugs mainly by causing modifications in the molecular arrangements and /or interactions between molecules in crystal lattices without any alteration in the chemical entity of API or compromising its pharmacological activity [7].

Meloxicam, is designated as 4-hydroxy-2-Methyl-N- [(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. Meloxicam is a class II NSAID and is used in the management of pain or inflammation caused by osteoarthritis and rheumatoid arthritis [8]. The property of rapid absorption and rapid onset is always desirable for analgesic agents. For class II drugs, increasing solubility and dissolution rate, which presents the rate-limiting step to drug absorption may cause a remarkable enhancement in clinical response [9]. Therefore, in this study cocrystal formation was screened with different coformers including tartaric acid, citric acid, oxalic acid dihydrate, and saccharin. In addition, ibuprofen was explored as a possible coformer for the production of drug-drug cocrystals and ultimately gain a beneficial therapeutic hybrid with meloxicam.

Materials and Methods

Materials

Meloxicam and Ibuprofen were purchased from (Ajanta, India). Citric acid and tartaric acid were obtained from (Panreac Quimica S.L.U., Barcelona). Oxalic acid dihydrate and sodium lauryl sulfate were purchased from (Fluka AG, Switzerland). Saccharin was purchased from (Sigma –Aldrich, Germany).

Synthesis of cocrystals

Fast evaporation method using a rotary evaporator was adopted to prepare the cocrystal formulations (Table 1). Meloxicam and coformers in a molar ratio of (1:1) and (1:2) were dissolved in a solvent mixture consisting of chloroform and methanol (50:50% v/v). Thereafter, the solvent was dried under reduced pressure, temperature of 55⁰C, and 100 rpm. Finally, round bottom flasks were scraped and powders were sieved and stored for further analysis.

Characterization of cocrystals

Differential scanning calorimetric (DSC) analysis

DSC was obtained using SAT PT-1000 Linseis instrument. Samples of pure meloxicam, coformers, and their corresponding formulations were loaded into hermetically sealed aluminum pans and heated at a rate of 10°C/min, and scanned in the range of 0-400 °C under argon atmosphere.

Powder X-ray diffraction (PXRD)

Using a Shimadzu X-ray diffractometer (XRD 6000) equipped with a Cu radiation source at 40 kV and 30 mA, X-ray spectra were obtained. Scanning was performed at ambient temperature from 5 to 80 degrees over 2ϴ drive axis, with a scan speed of 8 degrees/min and a continuous scanning mode.

FTIR

Using an FTIR spectrophotometer (Shimadzu FTIR-8400S) by the potassium bromide disc method, FTIR spectra were obtained. Briefly, samples of pure meloxicam, coformers, and their corresponding formulations were thoroughly mixed and triturated with potassium bromide. Then, the mixtures were pressed into compacts and analyzed at 400-4000 cm^-1.

In-vitro drug release study

Drug release study for the pure meloxicam and formulations (F1 –F9) was done using the USP Type II dissolution apparatus (Vanguard/ USA). Samples of 100 mg of meloxicam or its equivalent amount of cocrystals were weighed and placed in phosphate buffer (900 ml, pH 6.8) containing 1.5 % sodium lauryl sulfate and rotated at 37±0.5⁰C and 50rpm. 5 ml of samples were collected at each time interval and compensated with an equal volume of buffer solution. The withdrawn samples were filtered through the Whatman filter and spectrophotometrically analyzed at 360 nm. All release studies were performed in triplicates.

Results and Discussion

Differential scanning calorimetric (DSC) analysis

 Meloxicam DSC thermogram exhibited a sharp endothermic peak reflecting its melting point at 260.5⁰C [10]. The DSC thermograms for the prepared formulations displayed different thermal patterns compared to the pure meloxicam. Most formulations except formulation F1 recorded melting points that are lower and/or between those recorded for meloxicam and the coformers, attributed to the formation of new crystalline solids that are characterized by weaker intermolecular forces than the starting crystalline forms [11, 12]. The higher melting point displayed in formulation F1 has been recorded in literature, yet it is not a frequent observation in cocrystals [13]. The DSC thermogram of the selected formulation F6 is shown in (Figure 1).

PXRD

XRD patterns were analyzed for both the starting materials and the corresponding formulations. Pure meloxicam exhibited characteristic sharp peaks at 13.09⁰,14.94⁰,18.69⁰, and 25.83⁰ indicating its crystalline state [14]. Likewise, coformers showed diffraction patterns that reflected their crystalline nature.

The presence of additional peaks has been noticed in the X-ray spectra of all formulations (F1-F9), suggesting the formation of a new crystalline state [11, 15]. Figure 2 illustrates the diffraction spectrum of optimum formulation (F6), which exhibits distinct peaks at 8.407⁰, 16.28⁰, 18.01⁰, and 28.95⁰ that are not related to the drug or coformer.

Conclusion

It can be concluded that among the coformers explored throughout the study, oxalic acid dihydrate successfully produced cocrystals that achieved a significant enhancement in the dissolution rate compared to meloxicam.

Acknowledgments: The authors are deeply grateful for the support from the University of Mustansiriyah (www. uomustansiriyah.edu.iq), Baghdad–Iraq.

Conflict of interest: None

Financial support: None

Ethics statement: None