INTRODUCTION:

Pharmaceutical experts have been practicing various approaches to modify the physicochemical properties of the invented moieties. Co crystallization approach was successfully employed to prepare pharmaceutically useful cocrystals of an Active Pharmaceutical Ingredient (API) among various methods such as complexation, salt formation, polymorphism, etc. available.¹ Cocrystal is a multi-component system that composed of a drug and coformer (also known as cocrystal former or co crystallizing agent) in its crystal lattice.² A suitable stoichiometric ratio of drug and coformer is used to get a good yield of the cocrystals.³The main principle involved in the cocrystal formation is nonionic interaction between inter molecules like hydrogen bonding that forms between the drug and coformer, which are solids at ambient conditions.⁴

The properties like solubility, dissolution, and stability of a bulk drug can be enhanced by preparing the cocrystals without altering intrinsic covalent structure. Salts are different from cocrystals because protonation occurs in the salts, which are not present in cocrystals.Even though there is no method suitable for all drugs, liquid assisted grinding method is preferred in the preparation of cocrystals and salts over the other methods because the added liquid would accelerate the mobility of molecules of both API and coformers and decreases the thermodynamic energy barrier of cocrystal formation. Selection of coformers/excipients, from GRAS: Generally Recognized as Safe list released by USFDA, can be possible by using various screening techniques. Use of Hansen Solubility Parameter (HSP)⁵ as a tool to select coformers is novel for which the group contribution methods like Fedors, Hoy’s, and Van Krevelen approaches can be adopted.At least one functional group should be present in the coformer for the purpose of hydrogen bond formation with the API.The formation of hydrogen bonds can be predicted by molecular docking study.

Modafinil, a BCS class II drug having low solubility and high permeability, was selected as a model drug in the present study. Modafinil is a psycho stimulant (anti-depressant) drug that activates the wake promoting neurons and used in the treating narcolepsy as well as obstructive sleep apnea.⁶ In the current research, an attempt was made to prepare various cocrystals using modafinil followed by its characterization with instrumental analytical techniques.

MATERIALS AND METHODS:

Materials:

Modafinil drug was purchased from Matrix Laboratories Ltd., Hyderabad, India. All other coformers, excipients, and reagents were purchased from SD Fine Chem. Pvt. Ltd., Mumbai.

Screening of the coformers:

HSP is a pivotal method which can be used for preliminary selection of the coformers from the list obtained from GRAS and also for predicting the cocrystal formation. The solubility entities for the drug and 21 coforming agents were calculated by HSP utilizing methods such as Hoy’s method, Van Krevelen method, and Fedors method. The solubility parameters of the drug and selected coformers like boric acid, tartaric acid, cinnamic acid, and salicylic acid are listed in the Table 1. These coformers satisfy the requirement of at least one functional group in the structure to form strongest intermolecular bond i.e, hydrogen bond with the drug during cocrystal formation.

Table 1: HSP values for the drug and coformers:

Drug or Coformer	Solubility parameter (MPa^1/2)
Drug or Coformer	Fedors	Hoy’s	Van Krevelen
Modafinil	26.27	23.13	23.15
Boric acid	46.31	44.46	59.62
Cinnamic acid	23.22	25.06	22.27
Salicylic acid	29.90	28.89	27.70
Tartaric acid	36.17	34.38	37.62

Preparation of cocrystals:

The traditional method employed for the preparation of cocrystals was liquid assisted grinding. The drug and coformer/excipient (boric acid, tartaric acid, cinnamic acid, and salicylic acid) in the proportion of 1:1 molar ratio were placed in a mortar. The cocrystals were obtained on grinding the modafinil and coformer/excipient for 30-45 min by the simultaneous addition of a few drops of ethanol as a solvent. The solvent present on the surface was removed by placing the samples in a desiccator having calcium chloride for a time period of 2 weeks.

Melting point:

DBK Programmable Melting Point Apparatus Oil Bath (DBK Instruments, Mumbai) was used to determine the melting point of both the drug and the cocrystals via capillary tube method. The melting points of cocrystals were then determined at various time gaps up to three weeks and were recorded.

Saturation solubility studies in aqueous solvents:

The solubility of drug and cocrystals at saturation were determined in the distilled water. About 10ml of distilled water was transferred in to 50ml volumetric flasks. API and cocrystals were added additionally in each volumetric flask separately. The volumetric flasks were then shaken using cryostatic constant temperature shaker bath at 25ºC for 72 hours to obtain equilibrium. After reaching the equilibrium, samples were then pipetted out, filtered and then diluted using distilled water, and absorbance was taken at 217.6nm.

Dissolution studies:

The in vitro drug release studies of the drug and cocrystals were performed in distilled water for 1 hour in USP type II dissolution apparatus (USP XX III). The drug and cocrystals containing the drug equivalent to 50 mg were then filled in empty hard gelatin capsules. The filled capsules were forced to immerse in the dissolution medium using sinkers. Dissolution studies were carried out in 500ml of distilled water by maintaining the temperature of 37 ± 0.5ºC and paddle speed maintained at 100rpm. Samples were pipetted out at 10 min time gap for 1 h by replacing equal amount of fresh dissolution medium. The samples were then subjected to filtration through 0.45μm pore size filter. Furthermore, dilutions were done with distilled water and analyzed spectrophotometrically at 217.6nm using distilled water as a blank.

FTIR spectroscopy studies:

FTIR studies were performed for the API and its cocrystals by using FTIR (FTIR 8300, Shimadzu, Kyoto). The source delivered a radiation ranging from 4000 to 500 cm^-1having a resolution of 1 cm^-1. Absorption bands intensities were represented as % transmittance. KBR pressed pellet method was utilized for the preparation of sample. The samples were then mixed with powdered KBR in the proportion of 1:100. The mixture was compressed using 10tons/cm² pressure in vacuum to obtain a transparent pellet having 13mm diameter. The pressed pellet was then taken to IR chamber and the intensities of peak were then recorded.

Differential Scanning Calorimetric (DSC) studies:

Modafinil and its cocrystals were subjected to DSC studies by using differential scanning calorimeter (DSC-60 Plus, Shimadzu, Kyoto). Thermograms were obtained from aluminum pans utilizing indium metal as a standard. The rate of heating was 10°Cper/min under atmosphere containing nitrogen and the rate of flow was 80 ml/min. The energy needed to maintain the samples at specified temperature was then recorded on a chart.

Powder X-Ray Diffraction Studies (PXRD):

Cocrystals of modafinil and API were subjected to characterization at 25^oC using diffractometer- XPERT-PRO with Cu-Ka (λ=1.54060 Å). Values were collected in the angular range of 4^o to 50^o 2θ in a continuous mode scan utilizing a step size of 0.0170°2θ value at a scan speed of 1.0 min^-1.

Morphology Analysis:

The topographic data of the pure drug and its cocrystals were done by taking the micrographs of the same using SEM (JEOL JSM 6100, Japan) at SAIF, Punjab University. The sample was placed in stub, which was gold coated. The samples were then subjected to scanning in the instrument to procure the micrographs.

RESULT AND DISCUSSION:

Modafinil cocrystals formation prediction by HSP:

The formation of modafinil cocrystals with the selected coformers can be predicted if there is a difference in solubility parameters (Δδ) of less than 7MPa^1/2between the modafinil and coformer otherwise salts form. The Δ δ values for MOD-BOA (modafinil-benzoic acid, 20.04MPa^1/2, 21.33MPa^1/2, 36.47MPa^1/2 based on Fedors, Hoy’s and Van Krevelen, respectively) and MOD-TAA (modafinil-tartaric acid, 9.9MPa^1/2, 11.25MPa^1/2, 14.47MPa^1/2based on Fedors, Hoy’s and Van Krevelen methods, respectively) were found greater than 7, indicating the immiscibility of the drug and coformer suggesting the weak chances of cocrystal formation or chances of some other complex formation. In case of MOD-CIA (modafinil-cinnamic acid), the Δ δ value (3.05 MPa^1/2, 1.93 MPa^1/2, and 0.88 MPa^1/2based on Fedors, Hoy’s and Van Krevelen methods, respectively) was less than 7, revealed the possibility of formation of cocrystals. Similarly for MOD-SAA (modafinil-salicylic acid), the Δ δ value (3.63MPa^1/2, 5.76MPa^1/2, 4.55MPa^1/2 based on Fedors, Hoy’s and Van Krevelen methods, respectively) was also less than 7 showed higher chances of the cocrystals formation.Thus the selected acids fall into the two classes, one set of boric acid and tartaric acid with less chances of cocrystal formation (or more chances of some other complex formation) and another set of cinnamic acid and salicylic acid with more chances of cocrystal formation.

Characterization of modafinil cocrystals:

The prepared cocrystals were characterized by the following techniques.

Melting point determination:

Melting points of cocrystals, given in Table 2, were decreased when compared to that of pure drug giving a clue that some changes in the crystal lattice of cocrystals must have been taken place due to the interaction between coformer and the drug. However the effect of temperature on cocrystals melting was further assessed by DSC studies.

Aqueous saturation solubility studies:

All the cocrystals revealed remarkable increase in the solubility, might be due to lesser melting points of cocrystals than that of the pure drug (0.516 ± 0.0048 mg/ml) in distilled water. The highest solubility was found in MOD-SAA (2.563 ± 0.2074 mg/ml) with an approximately 5 fold increase in the solubility than the pure drug. The less solubility of the MOD-BOA and MOD-TAA than the other two cocrystals may be due to the formation of complexes predicted by HSP. The order of solubility of modafinil cocrystals/complexes obtained was MOD-SAA>MOD-CIA>MOD-BOA>MOD-TAA> pure drug (Table 2).

Table 2: The melting point and solubility data of the Drug/Co-crystals/Complexes

Drug/Cocrystals/ complexes	Melting point (^oC)	Mean solubility (mg/ml)
Modafinil	162.60 ± 1.154	0.516 ± 0.0048
MOD-BOA	137.3 ± 1.154	1.553± 0.1435
MOD-CIA	117.0 ± 0.987	2.270 ±0.1791
MOD-SAA	148.6 ± 1.570	2.563 ±0.2074
MOD-TAA	138.0 ± 1.547	1.485± 0.1156

(Mean ± S.D, n=3)

Dissolution studies:

Perusal to fig.1, the % drug release of modafinil from MOD-SAA (80.25% at 60 min) and MOD-CIA (57.71 % at 60 min) cocrystals were higher than that of the pure drug that released only 35.21 % of the drug at 60 min. Whereas % drug release from MOD-BOA and MOD-TAA are 32.15 % and 26.39 %, respectively at 60 min, the values were less than that of the pure drug. This decrease may be due to the formation of complexes that might have hindered the release of the drug into the dissolution medium.

Fig. 1: Dissolution profile of modafinil and its cocrystals/complexes

FTIR Spectroscopy:

FTIR spectroscopy was used to examine the characteristic hydrogen bonding between the drug and coformer since intermolecular hydrogen bond formation can cause distinguishable vibrational frequency shifts. The data derived from the spectra (Fig. 2) were mentioned in the Table 3. The spectra of MOD-BOA showed an increase in the vibrational frequency of –CH and –S=O might be due to the formation of salt or complex. In case of all others, the slight change in vibrational frequency of all the stretching bands may be due to the presence of weak hydrogen bonding between the drug and coformers/excipient. Analysis of the results of other instrumental techniques needs to be correlated with these results, which are explained in the later part of the paper.

Table 3: The data of FTIR spectra for characteristics of Drug/Cocrystals/Complexes

Drug/Cocrystal	Stretching bands, (cm^-1)
Drug/Cocrystal	-CH	-NH	-C=O	-S=O
Modafinil	3351	3169	1691	1374
MOD-BOA	3467	3192	1692	1450
MOD-CIA	3307	3164	1685	1401
MOD-SAA	3348	3157	1670	1330
MOD-TAA	3324	3027	1685	1368

Fig. 2: Spectra of (a) Modafinil, (b) MOD-BOA, (C) MOD-CIA, (d) MOD-SAA and (e) MOD-TAA

Morphology analysis:

The micrographs of pure drug and its cocrystals/complexes were obtained as shown in fig. 5 were used to study the topographic changes.A rod shape structure observed for the pure drug (fig. 05A)was clearly different in case of its cocrystals/complexes.

Fig. 5: SEM of (a) Modafinil, (b) MOD-BOA, (c)MOD-CIA, (d)MOD-SAA, and (e)MOD-TAA

CONCLUSION:

The work presented herein exemplifies how cocrystals/ complexes can generate novel crystalline forms of existing drug with different physical properties. Modafinil was targeted for cocrystal/complexes forms development with the goal of improving its solubility and dissolution. Liquid assisted grinding method was found an easy and satisfactory method in the preparation of cocrystals/complexes. The formation of modafinil cocrystals by using coformers namely cinnamic acid and salicylic acid were predicted by HSP calculations and successfully confirmed by assessing the results of FTIR, PXRD, DSC, and SEM. Similarly, the complexes prepared with boric acid and tartaric acids have not shown much improvement in the desired properties though they were formed as predicted by the HSP. Hence applicability of HSP for the determination of cocrystal/complex formation is valid.

ACKNOWLEDGEMENT:

The authors are heartfully thankful to Rajiv Gandhi University of Health Sciences, Bangalore for funding this project. The authors are highly indebted to SAIF, Punjab University for carrying out the characterization studies by various analytical methods.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Sinha AS, Maguire AR, Lawrence SE. Cocrystallization of nutraceuticals. Crystal Growth and Design 2015; 15(2): 984-1009.

2. Raheem Thayyil A, Juturu T, Nayak S, Kamath S. Pharmaceutical co-crystallization: Regulatory aspects, design, characterization, and applications. Advanced Pharmaceutical Bulletin 2020; 10(2): 203-12.

3. Jino ET, Usha YN Jagadish PC, Koteshwara KB. Design and characterization of valsartan co-crystals to improve its aqueous solubility and dissolution behaviour. Research Journal of Pharmacy and Technology 2017; 10(1): 26-30.

4. Yadav AV, Shete AS, Dabke AP, Kulkarni PV, Sakhare SS. Co-crystals: A novel approach to modify physicochemical properties of active pharmaceutical ingredients. Indian Journal Pharmaceutical Science 2009; 71(4): 359-70.

5. Mohammad MA, Alhalaweh A, Velaga SP. Hansen solubility parameter as a tool to predict cocrystal formation. International Journal of Pharmaceutics 2011; 407(1): 63-71.

6. Dauvilliers Y, Roth T, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy. Sleep Medicine 2017; 40: 53-7.

Received on 25.07.2020 Modified on 27.08.2020

Research J. Pharm. and Tech. 2021; 14(9):4891-4896.

DOI: 10.52711/0974-360X.2021.00850