INTRODUCTION:

Many new drug candidates are highly lipophilic, in which development of optimal oral and parenteral drug delivery systems is a challenging issue^1,2. Physicochemical properties of drug candidates in terms of aqueous solubility, permeability and stability are crucial in formulating an oral dosage form. The dissolution rate is highly affected by these physicochemical properties, which in turn, contributes to the fluctuated oral bioavailability of the orally administered drugs and hence reduces their efficacy^2-5.

Various approaches were designed to improve the solubility and dissolution rate of poorly soluble drugs BCS class II and IV such as micronization, cyclodextrin complexation, self-emulsion, salt formation, optimization of the pH and crystallization². Although each of those approaches enhances the dissolution rates, they are solely dependent on the nature of physicochemical properties of the drug molecule. For instance, micronization enhances the dissolution rate by increasing the surface area exposed to the solvent, while it fails to increase the equilibrium solubility and the electrostatic forces between the extensively fine particles retard the dissolution^6-8. Cyclodextrin complexation requires a rapidly dissolved drug in the gastrointestinal tract⁹. Most of the drug molecules are formed as salts; however, there are some limitations of salts compared co-crystals. As salt formation is confined by acid-base reaction, it is governed by suitable pK_a value, while co-crystals can be formed even without ionizable group¹⁰.

Co-crystal engineering is considered as a fruitful approach for developing a wide range of APIs and improving their kinetic solubility, dissolution rates and subsequent bioavailability^11-13. The API is incorporated into suitable pharmaceutical molecules, which are generally expressed as co-formers, to formulate the crystal lattice through non-covalent adhesive interactions (H-bonding). This crystal lattice or a multicomponent pharmaceutical crystal modifies the physicochemical properties of the API while maintaining its intrinsic activity. The incorporated components are all in solid state under the ambient conditions and co-exist as stoichiometric ratio of the targeted molecules¹⁴. Co-formers utilized for crystal synthesis include tartaric acid (TA), citric acid (CA), succinic acid (SA), glutaric acid (GA) and fumaric acid (FA)¹⁰. A general framework of co-crystallization results in various solid forms including co-crystals, co-crystals polymorphs, co-crystal hydrates (solvates), co-amorphous solids and eutectics^15,16.

The most interesting advantage of the co-crystal synthesis is that it is suitable for all types of molecules, including ionizable and nonionizable, and the incorporation of preservatives and other pharmaceutical excipients^15,17. Many factors influence the formulation of co-crystals such as ΔpK_a value (difference between pK_aof the API and the co-former) where the co-crystals are formed when ΔpK_a is negative as no protons are transferred. However, it is not an accurate way for confirming the nature of the solid formed^18,19. Other factors that influence the crystal formation include the ability of the API and co-former to form hydrogen bonds, the existence and position of certain functional group on the API that allows the interaction with the co-former^12,20. Also, the length of carbon chains of the co-formers (longer chains retard the co-crystallization)²¹ and the nature of the solvent to dissolve the API and co-former influence the crystal formation^22,23.

Diverse approaches of crystal engineering are reported in the literature that can be utilized to manipulate the solubility and dissolution rate of sparingly soluble drugs and to tailor specific physical and chemical properties. Few traditional methods were proposed for crystal synthesis based on solution and grinding²⁴. The solution-based co-crystallization includes solvent evaporation, anti-solvent addition, slurry conversion and solution crystallization^25,26. Grinding methods can be either neat/dry or solvent drop²⁷. Other techniques include ultra-sound assisted crystallization, supercritical fluid atomization, spray drying and hot melt extrusion⁵. The fundamental concept of these aspects is to equilibrate the surface of molecule with the solution. Hence, the low aqueous solubility can be dealt by crystal engineering to serve two purposes, improving the bioavailability and developing robust pharmaceutical products¹³.

Acyclovir is a well-known antiviral agent used for treatment of various viral infections such as herpes and varicella^28-30. According to the Biopharmaceutics Classification System (BCS), acyclovir³¹ has limited absorption through the gut wall and its bioavailability accounted for only 15-30% with a peak plasma concentration of 2.5 hours^32,33. Examples are also available from the literature related to solubility enhancement of acyclovir and other drugs using co-crystal technique^36-46.

The current work aims to enhance the solubility of acyclovir by forming co-crystals using microwave-assisted solvent evaporation. This technique works by modifying chemical structure and hence the physicochemical properties of various pharmaceutical products³⁴. The incorporation of microwave for crystal synthesis is a valuable tool to produce small molecules in fraction of time, which is much shorter than traditional thermal method. Acyclovir crystals were characterized by Fourier transform infrared spectra (FTIR), X-Ray Diffraction, UV-spectroscopy and dissolution studies.

MATERIAL AND METHODS:

Chemicals and reagents:

Acyclovir API was a gift from Cipla Limited (Mumbai, India) while the co-formers were purchased from Fisher Scientific and SDFCL (Mumbai, India) including tartaric acid (TA), citric acid (CA), succinic acid (SA), glutaric acid (GA) and fumaric acid (FA). Other excipients were utilized for crystal synthesis including glacial acetic acid (GAA) from SDFCL (Mumbai, India), propylene glycol from Laboratory Rasayan (Rajkot, India), triethanol amine buffer from Fisher Scientific (Mumbai, India).

Determination of Acyclovir Solubility:

Standard Stock Preparation:

Accurately weighed amount of 100 g of acyclovir was transferred to a 100-mL volumetric flask and 70mL of water was added, sonicated to dissolve for 5 minutes. Then it was diluted with water and mixed until 1000 ppm was obtained.

Standard Preparation:

The above solution was further diluted to make 100ppm solution and scanned at 200-400nm using UV-spectrophotometer (Perkin Elmer Lambda 25, USA).

Standard Calibration Curve for Total Solid (TS) in Water/Phosphate Buffer:

From the above standard stock solution, 1mL was pipetted out and diluted up to 100mL with water to obtain 10ppm. Different volumes were pipetted out from the previous solution were further diluted up with water to obtain 2ppm, 4ppm, 6ppm and 8ppm solutions. Each of the resulted solutions were analyzed using UV-spectrophotometer at 252nm. Linearity curve was obtained by plotting the concentration (ppm) vs the absorbance. The exact previously mentioned procedures were applied using phosphate buffer as a solvent instead of water.

Co-Crystals Formation:

Solvent Evaporation (SE):

The API and co-former were weighed in an equimolar ratio and transferred to a beaker. The solvent was added to the mixture and heated on magnetic stirrer at 80℃ for 10-15 min until a clear solution was obtained. The resultant solution was kept for cooling overnight and subjected to drying in a vacuum oven until the solvent completely evaporates (Table 1).

Microwave-Assisted Solvent Evaporation (MASE):

The same equimolar ratio of API and co-former were prepared and transferred to a glass vial with the solvent. The solution was placed in microwave synthesizer (CEM) in a closed vessel at 80℃ and 100W until a clear solution was obtained. Later, the resultant solution was cooled then dried in a vacuum oven [Table 1].

Table 1: Experiment trails with different co-formers and solvents

Sr. No.	ACV: Co-former (X:Y)	Co-solvent	Method
1	ACV: TA (1:1)	Water	SE
2	ACV: TA (1:1)	Methanol	SE
3	ACV: CA (1:1)	Water	SE
4	ACV: SA (1:1)	Water	SE
5	ACV: GA (1:1)	Glacial A. A	SE
6	ACV: TA (1:1)	Glacial A. A	SE
7	ACV: TA (1:1)	Glacial A. A	MASE
8	ACV: FA (1:1)	Glacial A. A	SE
9	ACV: GA (1:1)	Glacial A. A	SE

Characterization of The Formulated Co-Crystals:

The physical properties of the co-crystals were evaluated by melting point apparatus, super-saturation technique for solubility, dissolution apparatus and differential scanning calorimetry. Structural characterization was performed by FTIR and Powder X-ray Diffraction.

Physical Characterization of Co-Crystals:

Melting Point:

Melting point of pure API Acyclovir, co-formers and co-crystal were obtained by capillary method.

Solubility Study:

The solubility of the API and co-crystals were determined by saturation technique. Samples were prepared by adding excess powder into a 1.5mL Eppendrof tube containing 1 mL of water until it exceeds the saturation. At room temperature, all Eppendrof tubes were kept on an orbital shaker for 24 hours. The solutions were filtered, diluted with water and absorbance was measured at 252nm using UV-spectrophotometer. The average absorbance values of the co-crystals were compared to that of the API.

Dissolution Study:

The dissolution study was carried out using the United State (USP) Apparatus 2, Paddle apparatus from Erweka (Heusenstamm, Germany). The API and co-crystals were powdered and sieved through a #60 sieve. The apparatus was maintained at 37±0.5℃ and operated at 50rpm. Dissolution was carried out using API and co-crystals equivalent to 200mg of Acyclovir in 900mL of water as dissolution medium. The concentration of dissolved drug was taken at different time intervals (5, 10, 15, 30, 45 and 60 min) and measured with UV-Spectrophotometer.

Differential Scanning Calorimetry (DSC):

Thermal analysis of API, co-former and co-crystal were recorded individually on DSC (Metler Toledo, USA). The samples were scanned at 10℃ per minute. Rate of heating employed was 10℃ per minute over a temperature range of 50-300℃ with nitrogen purging.

Structural Characterization of Co-Crystals:

Fourier Transform Infrared (FTIR):

The FTIR spectra of acyclovir co-crystals was recorded in the frequency range 400-4000 cm^-1 by KBr pellet method using the FTIR from Perkin Elmer (Waltham, Massachusetts, USA) at a resolution of 4 cm^-1and scanning speed of 2mm/s. The recorded FTIR spectra were compared with the reference acyclovir spectrum.

The Proposed method was validated as per the ICH guidelines.

Powder X-Ray Diffraction:

This technique enabled preliminary characterization of materials in powdery forms that consist of fine grains of crystalline materials. Multi-scans were performed over 10-60 min and recorded over 20-range 0-40°.

Microscopic and Particle Size Analysis:

This technique enables differentiation and evaluation of crystal structure and size with a high resolution (400x) to fulfil the basic purposes for further screening of the crystals using the Motic BI advanced (Hong Kong).

UV-Spectrophotometric Analysis of Acyclovir Co-Crystals:

An accurately weighed amount of the co-crystals equivalent to 100mg of acyclovir was transferred to a 100-mL volumetric flask. A volume of 70mL of deionized water was added and after sonication, the suspension was made up to the mark with the same solvent. After 100 times of successive dilutions, the absorbance was measured at 252nm and % content was calculated.

RESULTS AND DISCUSSION:

Solubility:

Within 24 hours of super-saturation, the solubility of all combinations (API with co-former) in water by solvent evaporation technique (SE) is shown in Table 2 as the following: ACV:TA (1:1): 3.62mg/mL, ACV:CA (1:1): 2.975mg/mL, ACV:SA (1:1): 2.24mg/mL and ACV:GA (1:1): 3.414mg/mL. Among all studied co-formers, tartaric acid was selected as the most suitable co-former for acyclovir in which the percentage of solubility was enhanced with TA (44.0 %) compared to other co-formers. This can be justified as the co-crystal solubility, is highly dependent on its components. So, for improved solubility of poorly soluble drug, it is essential to select a co-former with high aqueous solubility [35,36]. In acidic medium (glacial acetic acid), both the SE and MASE techniques were carried out using the selected co-former (TA). The results showed that the percentage solubility of acyclovir with TA by SE and MASE in acid was highly improved to the triple of that in water by 140.0% and 120.0%, respectively. This was consistent with previous study, where acidic medium strongly enhances the drug solubility in its co-former¹⁰.

Table 3: Optimization of Microwave Synthesis

Sr. No.	Name	Qty Taken (mg)	Solvent (mL)	Power	Time (sec)	Result	Amount Obtained (mg)
1	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (2 mL)	100W	60	Crystals obtained	360
2	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (2 mL)	100W	60	Crystals obtained	363
3	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (0.5 mL)	100W	60	Crystals obtained	367
4	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (0.5 mL)	100W	30	Crystals obtained	363
5	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (0.5 mL)	100W	10	Crystals obtained	369
6	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (0.5 mL)	100W	5	Crystals not obtained	-
7	ACV:TA (1:1)	ACV(225)+ TA (150)	Glacial acetic acid (0.5 mL)	150 W	5	Crystals not obtained	-

Dissolution Rate:

The dissolution test was performed on the selected co-crystals of ACV:TA (1:1) compared to the pure acyclovir based on the solubility test. Table 4 represents the percentage of drug released from the plain acyclovir drug compared to the acyclovir co-crystals at each time interval. After 60 min, acyclovir co-crystals released 85.0% of acyclovir, while only 59.0% of the acyclovir was released from the plain drug as shown in Figure 1^10,37. This means that microwave-assisted solvent evaporation is a promising method that enhances the dissolution rate of acyclovir.

Table 4: % Release of Acyclovir and Acyclovir co-crystals using (water)

Sr. No.	Sampling time (min)	% Release of acyclovir from co-crystals ± % RSD	% Release of acyclovir from plain drug ± % RSD
1	5	11.0 ± 1.0	9.0 ± 1.1
2	10	28.0 ± 4.1	13.0 ± 4.1
3	15	48.0 ± 0.2	17.0 ± 0.2
4	30	72.0 ± 0.6	42.0 ± 0.6
5	45	80.0 ± 0.2	51.0 ± 0.2
6	60	85.0 ± 0.2	59.0 ± 0.2

Figure 1: % Release of acyclovir from plain drug and co-crystals

DSC Measurement:

The DSC enables the determination of solid-state interactions between two or more molecules and the thermodynamic changes (endo-and exo-thermic heat) can be evaluated by generation of heat energy to the co-crystals. Thermodynamic aspects can be determined for the solids as well as in the co-crystals structure due to the physical interactions between the compounds^{38, 39}. The DSC thermograms of acyclovir, TA and ACV:TA (1:1) can be seen in Figure 2. The endothermic peak of acyclovir was 258.6 ℃, which indicates the melting point of acyclovir, and after around 260.0 ℃, at which acyclovir is decomposed. Tartaric acid (TA) showed a sharp endothermic peak at 177.4 ℃. On the other hand, ACV:TA co-crystals represented different pattern and intensity (different melting transition) compared to the thermogram of the individual components, which reflects the interaction between acyclovir and the co-former (TA) that results in co-crystal formation. The slightly lesser and distinct intensity of the enothermic peak of the co-crystals (160.0 ℃) is due the change in the crystal lattice of acyclovir upon reaction with the co-former, which ends up with relatively different co-crystal lattice⁴⁰. This was consistent with previous studies, as the co-crystallization results in distinctively lower melting point that that of the individual components.

Microscopic and Particle Size:

The formulated co-crystals appeared as needle shaped and their size was small compared to the starting materials as shown in Figure 5. Although the micro-particles had irregular shapes but sized within the micrometric range (1-1000μm) with an average of 16.7μm. Micro-sized particles provide larger surface area, where atoms become closer to the core and more reactive, thus drives the solubility profile to higher values as previously was revealed by Mahmood et.al.⁴⁵

Figure 5. Microscopic results of ACV:TA (1:1), 10×100x

UV-Spectrophotometry Analysis:

The UV-scan of acyclovir appeared at a peak of 252.66 nm. Upon plotting the absorbance versus the drug concentration in water or phosphate buffer, a linear curve was obtained up to 10ppm; providing the following linear equations y=0.0528x+0.023 (R²= 0.9994) and y=0.0527x-0.0044 (R²= 0.9956), respectively. Acyclovir content in the co-crystal (ACV: TA) was measured in triplicate and found to be 62.5%. This was convincing as the molar ratio of the reacted acyclovir with TA was 1:1, which was determined according to the theoretical percentage of both components (ACV:60.0% and TA:40.0%)⁴⁶.

CONCLUSION:

In the present work, acyclovir co-crystals were successfully prepared using the microwave-assisted solvent evaporation method. The proposed method is interesting as less solvent and less time were consumed for the successful reaction. The newly formed co-crystals were characterized by several physicochemical properties (Solubility study, dissolution, UV spectrophotometry, FTIR, PXRD, DSC and microscopy), which confirm the formation of co-crystals. The solubility of acyclovir was highly improved when tartaric acid was used as a co-former with acyclovir in an equimolar ratio (1:1). Thus, this study revealed that co-crystallization of acyclovir is a promising pharmaceutical technique that positively improves its solubility.

ACKNOWLEDGEMENT:

Authors V.L and N. S would like to thank SVKM’s NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, Mumbai for providing research facility. Authors wish to thank Cipla Ltd for gift sample of drug. Authors R.R.B, A.A and S.Z.A would like to thank the Dean’s office of College of Pharmacy and Health Sciences, Ajman University for their support extended towards this project and writing this manuscript.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 02.12.2019 Modified on 07.03.2020

Research J. Pharm. and Tech. 2020; 13(12):5979-5986.

DOI: 10.5958/0974-360X.2020.01043.4

Sr. No.	Solvent	Name	Method	Solubility (mg/mL)	Percentage Increase
1	Water	ACV: TA (1:1)	SE	3.6	44
2	Water	ACV: CA (1:1)	SE	3.0	19
3	Water	ACV: SA (1:1)	SE	2.2
4	Water	ACV: GA (1:1)	SE	3.4	36
5	Glacial A. A	ACV: TA (1:1)	SE	6.0	140
6	Glacial A. A	ACV: TA (1:1)	MASE	5.5	120
7	Glacial A. A	ACV: FA (1:1)	SE	2.6	4