INTRODUCTION:

Efavirenz (EFA) is a vital non-nucleoside reverse transcriptase inhibitor (NNRTI) for treating HIV^1,2. Its bioavailability, around 40-45%, may be limited due to its crystalline nature^3,4. Boosting surface area could enhance solubility but risks stability issues due to high surface energy. Nonetheless, EFA's efficacy in HIV treatment, either standalone or combined with other antiretrovirals, is proven. To counter low bioavailability, cocrystallization emerges as a promising technique⁵. Ascorbic acid (AA) plays a key role as a cocrystal former due to its ability to form hydrogen bonds, improving solubility, bioavailability, and stability of drugs^6,7,8.

Additionally, AA's antioxidant properties can prevent drug degradation, potentially extending shelf life. Research explores AA's multifunctional role in pharmaceutical formulations. By using solvent evaporation, a straightforward method in pharmaceutical cocrystallization, the active ingredient and coformers are dissolved in a solvent and slowly evaporated under controlled conditions. This process yields high-quality cocrystals with defined structures, scalable for industrial use and compatible with various solvents and coformers. Ongoing studies focus on developing new cocrystals with improved therapeutic properties, utilizing AA's potential as a versatile excipient^9,10.

The present study aims to predict the intermolecular interaction between EFA a AA using in situ models. To enhance the solubility, dissolution rate, and stability of EFA, the approach of cocrystallization with AA was employed. Given that AA exhibits various pharmacological activities, including antioxidant, anti-inflammatory, anti-Alzheimer, and anticancer effects, its addition could potentially enhance the biopharmaceutical properties of EFA. The introduction of AA may induce a change in the polymorphic nature of EFA molecules, which can be verified through thermal and crystallographic analytical studies.

MATERIALS AND METHODS:

The EFA was provided by Hetero Labs limited, India, while AA was purchased from Loba Chemical, India. Ethanol of research grade quality was obtained from Research Lab Finechem industries, India. Analytical grade distilled water, chemicals, and reagents were used throughout the investigation.

In- silico studies:

Pharmacological activities of EFA and AA was predicted by using PASS online (Prediction of Activity Spectra for Substances) software¹⁰. The values of Pa (probability of compound to be active) and Pi (probability of compound to be inactive) were obtained for prediction¹². The molecular internal environment and intermolecular interaction of the drug–drug multicomponent crystal was explored using Hirshfeld surface analysis with the help of crystal Explorer 21 software. Virtual physical interaction between EFA and AA was studied by using V-Life MDS 4.6 software. Suggested interaction by software were subjected to study with the help of DSC, XRD and NMR analysis^13,14.

Experimental work:

Phase solubility study:

The phase solubility studies of EFA in distilled water were conducted using a method described by Higuchi and Connors¹⁴. To study the effect of various concentrations of AA on solubility, excess EFA was added to 10 ml distilled water with and without AA. The binary suspension was then placed on a mechanical shaker and stirred for 48 hours at room temperature. The filtrate obtained was filtered and analyzed using UV spectroscopy at 248nm after necessary dilutions^15,16,17. The stability constants, Kc, were calculated from the straight-line portion of the phase solubility diagram according to the Higuchi-Connors equation¹⁸:

Kc= slope/(Intercept x (1-slope))

By analyzing phase solubility data at varying temperatures, thermodynamic parameters for complex formation can be calculated using the Van't Hoff equation. This allows for determination of enthalpy (ΔH) and entropy (ΔS) changes based on stability constant variations with temperature¹⁹.

In Kc= - ΔH /RT + ΔS /R

Preparation of cocrystals:

To prepare cocrystals, EFA and AA were mixed in a desired stoichiometric ratio, ground with ethanol in mortar pestle, and then stirred at 1500rpm with a fixed amount of ethanol at different temperatures²⁰. The resulting mixture was left to evaporate for 24 h and crystalize, if necessary, placed in a hot air oven or desiccator maintained at 45°C and the cocrystals were collected, stored, and used. The batches prepared using three levels of dependable variables are listed in Table 1.

Table 1: formulation batches of EFA

Sr. No.	Batches	AA: EFA ratio	Temperature (K)
1	E₁	0.5	293
2	E₂	0.5	303
3	E₃	0.5	313
4	E₄	1	293
5	E₅	1	303
6	E₆	1	313
7	E₇	2	293
8	E₈	2	303
9	E₉	2	313

Saturation solubility studies:

To determine saturation solubility, excess cocrystal were added to 10 ml of distilled water in solubility tubes and shaken by a mechanical shaker at 100 rpm for 48 hours. The filtrate was filtered and analyzed using UV spectroscopy at 248 nm, following the Higuchi and Connors method^21,22.

Fourier transformation-infrared spectroscopy (FTIR):

FTIR spectroscopy was used to analyze the functional groups and vibrational frequencies of samples. Each functional group produces a unique absorption band, which was recorded using a BRUKER-ECO-ATR-ALPHA FTIR spectrometer. The recorded spectra were used for qualitative and quantitative analysis of the sample in the spectral range of 600 to 4000 cm^-1with 24 scans^{23,
24, 25}.

Percentage drug content:

For the determination of percentage drug content, 20 mg of the formulated crystal particles were weighed and stirred in 10 ml methanol at 100 rpm for 24 hours. Filtrate was analyzed using a Shimadzu UV spectrophotometer at 248 nm after necessary dilutions. The percentage drug content was calculated using the formula^26,27.

% Drug content = (Actual drug content) / (Theoretical equivalent drug taken) × 100

Differential scanning calorimetry (DSC):

Thermal analysis wascarried out using Shimadzu DSC60, Japan witha heating rate of 20°C/min within temperature range of 40-260°C^{28, 29}.

X-ray powder diffractometry (XRPD):

It was obtained using a BRUKER D80 X-ray diffractometer (Switzerland) equipped with a Cu tube anode, with scanning performed over the range of 10-90°/2θ. The instrument settings included a generator tension (voltage) of 30 kV and a generator current of 10 mA^30,31,32.

Nuclear Magnetic Resonance (NMR):

In this study, the NMR spectra were recorded using a Bruker Advance 300 spectrometer, Switzerland at 300 MHz, with a spectral window of around 10000 Hz. The samples were dissolved in deuterated chloroform (CDCl3) solvent and TMS (tetramethylsilane) was used as the internal standard^3,33.

Scanning electron microscopy (SEM):

Morphological study was carried by using SEM (Carl Zeiss, model number Supra 55, Germany) 1K, 5K, 10K and 25 K time’s magnification^34,35,36.

Dissolution study:

To evaluate dissolution, a type 2 disso apparatus (LABINDIA Dissolution test apparatus, DS 8000) was employed using 900ml simulated phosphate buffer of pH 7.4 maintained at s 50rpm stirring rate and 37 ± 0.5⁰ C temperature. At specific time intervals, 5 ml of an aliquot was withdrawn and analysed by via UV spectroscopy^37,38,39.

Stability study:

Accelerated stability study was conducted for 90 days in stability chamber (REMI SC 16S) set at 40°C and 75% relative humidity^40,41,42.

RESULT:

Biological activity were predicted in table 2 for EFA having Pa value more than 70% and for AA having Pa value more than 80%. Intermolecular interaction of multicomponent EFA and AA crystal was studied from Hirshfeld surface analysis as shown in figure 1 A and B³⁵.Virtual physical interaction between EFA and AA were analyzed as shown in figure 1 C.

Table 2: Predicted activity of EFA and AA

EFA
Pa	Pi	Activity
0.898	0.003	Antiviral (HIV)
0.881	0.004	Antiviral
0.879	0.001	HIV-1 reverse transcriptase inhibitor
0.853	0.003	Biliary tract disorders treatment
AA
Pa	Pi	Activity
0.948	0.002	Vasoprotector
0.928	0.003	Antioxidant
0.896	0.001	Procollagen-lysine 5-dioxygenase inhibitor
0.894	0.005	Acute neurologic disorders treatment
0.889	0.001	Oxygen scavenger
0.881	0.009	Ubiquinol-cytochrome-c reductase inhibitor

Phase solubility:

EFA, practically insoluble drug, showed saturation solubility of 8.5µg/ml in distilled water. As per figure 2 (1), it has been increased with concentration of AA, but rate of enhancement was reduced after 0.06mM. Increase in solubility with concentration of AA and temperature was generated as per figure 2 (2). Change in enthalpy and entropy was calculated by integrating the values in the Van’t Hoff equation from (figure 2 (3)) plot of In Kc versus 1/T (K).

IR study:

IR spectroscopic study showed different bond interactions in different chemical environment in figure 3 (1).

DSC Result:

DSC showed sharp endothermic peaks at melting point temperature and shifting towards lower value due to changed polymorphism in figure 3 (2). It showed absorption peaks in the range of 100⁰C to 275⁰C for EFA, AA and formulation.

Figure 1: Hirshfeld surface analysis of A: EFA; B: AA and C: Virtual interaction between EFA and AA

Figure 2: (1): Phase Solubility study; (2): Effect of temperature on stability constant; (3): Van’t Hoff plot for complex formation

XRD Result:

As shown in Figure 3 (3), EFA and its formulations exhibited maximum relative peak intensity at different 2θ values, indicating their crystalline nature. The peak characteristics were determined according to Table 3.

Table 3: XRD Peak characteristics of EFA and formulation: E₆ batch

Peak Characteristics	EFA	Formulation
2θ with maximum relative intensities	6.13, 24.91, 21.26, 20.05, 29.59, 14.16	28.07, 6.22, 25.28, 21.36, 30.05, 19.85, 14.26, 20.13, 40.32, 19.34, 37.51, 16.91, 32.49, 35.56
Average crystalline size (A⁰)	224.95± 26.72	288.54±30.69
Average surface area (eta L/mL)	0.6624±0.3	0.5458 ± 0.3

SEM Result:

Images of Pure EFA and EFA in different formulations with varying magnifications were presented in Figure 3 (4). These images provide valuable insights into the surface morphology of the materials and can aid in further studying their properties.

NMR Result:

The NMR spectra for different protons present in the given batches were depicted in Figure 3 (5), where sharp peaks were observed. The splitting of these peaks was a result of the interactions between neighboring protons in the chemical structure of the compound.

Dissolution rate study:

Dissolution rate of all batches and EFA were studied using Disso apparatus and plotted as per figure 4(1). Based on release kinetics for all batches, optimized batch was determined from figure 4(2). Coefficient of regression for all batches were calculated as per table 4. E₆follows maximum drug release with Higuchi release kinetic model and compared with release kinetic of EFA⁴³.

Saturation solubility studies:

Figure 5 (1) illustrates the saturation solubility of all the formulation batches with OLM.

Drug Content:

Drug content of all batches were found in the range of 89.64 to 99.9% in table 5.

Stability study:

Percentage drug content was determined in comparison with duration as shown in figure 5 (2).

DISCUSSION:

According to the predicted activity, there was a difference in action between EFA and AA. This suggests that the two compounds would not interfere with each other, which was confirmed by FTIR analysis. Additionally, the activity of AA was observed to assist EFA in its biological action⁴⁴.Both multicomponent EFA and AA crystals showed intermolecular interaction with intermolecular distance between 1 to 5 A⁰. It gives information regarding compactness and available functional group for interaction between EFA and AA.AA showed 72 van der Waal, 16 hydrophobic and 1 hydrogen bonding interactions with EFA drug. Interatomic distance might give the information regarding strength of interaction. Interatomic distances in the range of 2-4 A⁰, 1-3 A⁰ and 1.68 A⁰ revealed the presence of Van Der Waal, hydrophobic, and hydrogen bond interactions, respectively. It was also predicted from the available sites of EFA and AA with Hirshfeld surface analysis.

Phase solubility:

Increasing EFA concentration and temperature enhanced solubility, aiding in determining thermodynamic parameters. ΔH and ΔS were -17.08 KJ mol^-1 and -67.44497 J mol^-1K^-1, respectively. ΔH indicates interaction strength; its negativity signifies exothermic, heat-releasing complex formation. ΔS denotes entropic factors; its negativity suggests a more ordered complex with fewer possible arrangements compared to its components.

Saturation solubility:

Formulations showed higher EFA solubility than pure EFA. Temperature increased solubility, but the effect plateaued with moderate AA levels. Higher evaporation temperatures accelerated crystallization. However, at high temperatures with maximum AA, EFA became trapped in the co-crystal, complicating drug separation from AA.

FTIR:

The molecular structure of EFA contains a central indole ring system, which is linked to a substituted benzoxazinone ring system through an ether linkage. IR spectroscopy show sharp single peaks at 3314.28 cm^-1, 1600.67 cm^-1, 1745.63 cm^-1, 1189.93 cm^-1 and 1080.05 cm^-1 indicates cyclic secondary amine (-NH-), δ- lactam (cyclic amide), δ- lactone (-CO-O-), -CO- stretching in ketone group and –CO- stretching with cyclic ether. As well as peak present at 2883.31 cm^-1, 2355.53 cm^-1, 1494.54 cm^-1 and 746.89 cm^-1 shows absorption peak for =C-H stretching, carbon triple bond, aromatic stretching of –C=C- and aromatic benzene ring. Presence of peak at 2245.84 cm^-1 might be due to combination of two overtone peak of aromatic double bond with benzene ring.

AA, anti-oxidant, showed slight broad peaks at 3311.44 cm^-1, 28.94.46 cm^-1, 1748.09 cm^-1 and 1645.35 cm^-1 indicating presence of alcoholic bond, -C-H stretching, α, β conjugation with lactone and –C=C- stretching bond in structure respectively. It also showed two peaks at 1016.28 cm^-1 and 1110.03 cm^-1 for –C-O stretching of primary and secondary alcoholic bond in structure. Presence of all above peaks and absence of any extra significant peak physical mixture and formulation of EFA and AA indicates no any chemical interaction. Thus there was is no any modification to benzoxazinone ring, indicating no change in antiviral activity. As per virtual interaction between CH with –C=0 and alkynyl group, indicates enhancement of solubility and bioavailability.

Percentage drug content:

Drug content was increasing with AA and temperature, but effect of temperature was very small. At higher concentration of AA was bound strongly with EFA, so showed reduced drug content in E7, E8 and E9 than E6.

DSC:

Thermodynamic study of EFA showed two different polymorphic forms I and II structures with different endothermic peaks. Thermal analysis of EFA showed sharp endothermic peak at 138.14⁰ C with change in enthalpy (ΔH) of 41.31 J/g which indicates presence of polymorph I. AA has sharp endothermic peak at 195.22⁰C with ΔH of 512.7 J/g. This reveals the crystalline nature of solid. EFA and AA have got decompose above 280.71⁰C and 238.27⁰C respectively. As per literature, polymorph II of EFA has lower melting point and enthalpy than polymorph I. In this present formulation of EFA showed endothermic peak at 135.98⁰ C with ΔH of 48.29 J/g and 192.67⁰C with ΔH of 130.3 J/g. This shifting of peak towards lower values which might indicates conversion of one polymorphic form to another by changing physical properties.

XRD:

Varied relative intensities of formulation were observed at varying 2θ values. This might result from change of polymorphic structure of EFA into most stable form II. XRD also showed change in average crystalline size and average surface area of EFA in formulation. Peak parameters of EFA, such as the peak position, relative intensity, and crystallite size, and surface area was altered due to presence of AA which could provide valuable information about the crystalline structure of the sample.

NMR:

1H NMR spectrum confirms EFA's structure and proton positions. The spectrum displays peaks between δ 0.5-3.0 ppm for protons on aliphatic and aromatic rings, and between δ 7.0-9.0 ppm for aromatic protons. Chemical shifts and multiplicities vary based on experimental conditions, like solvent and sample concentration.

SEM:

EFA was present in micronized with regular crystalline form representing characteristic nature of polymorph I. This form might get changed in more stable polymorph II form present in columnar or somewhat needle shaped. This confirmed interaction between EFA and AA.

Dissolution study:

Due to crystalline nature and polymorphic form, percentage cumulative drug release for EFA was 22.45 %. Out of all batches, E₆ showed maximum percentage cumulative drug release of 84.10 %. Enhanced dissolution rate, about 3.75 times, was might be due to transformation of polymorph I form to polymorph II.

Stability study:

The drug content percentage of EFA, E6, and their physical mixture decreased over time, suggesting that an accelerated environment was not optimal for these formulations. However, the impact was least significant for the E₆ batch than others.

Figure 3: (1): FTIR peaks; (2): DSC; (3): XRD; (4): SEM; (5): NMR; (6): Dissolution profiles of EFA and all formulated batches; (7): Release kinetic model of EFA and E₆ batch (A: First order kinetics, B: Korsmeyer Peppas, C: Zero order, D: Higuchi model and E: Hixon-Crowell model); (8): Saturation solubility study for all formulation batches and (9): Percentage Drug content for stability study (EFA: Efavirenz drug; AA: Ascorbic acid; PM: Physical mixture of EFA and AA; FB/formulation/ EFA F: E₆ formulation batch)

CONCLUSION:

In conclusion, this study demonstrated that the less stable polymorphic form I of EFA belongs to BCS II due to its crystalline nature. Insilico study predicted that the interaction between EFA and AA will be enhanced at higher temperatures. Phase solubility analysis suggested that the solubility and stability of the formulation would be positively affected by this interaction. Compatibility of all batches with AA at variable temperatures was confirmed by FTIR and NMR, and the change in crystalline nature of EFA in the formulation was confirmed by DSC, XRD, and SEM. The dissolution rate of E6 batch was enhanced by 3.75 times compared to pure drug due to the shifting of polymorph I form to II, which is more stable. Therefore, the solvent evaporation method using AA at higher temperature was found to be suitable for the cocrystallization of EFA.

CONFLICT OF INTEREST:

There is no any conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

Authors thank Hetero Labs for providing the drug sample and the principals of Satara College of Pharmacy and Government College of Pharmacy for providing necessary facilities for research. They also acknowledge the contribution of the Principal of Late Dadasaheb Chavan Memorial Institute of Pharmacy.

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Received on 27.04.2023 Modified on 02.08.2023

Research J. Pharm. and Tech 2024; 17(1):213-221.

DOI: 10.52711/0974-360X.2024.00034

Release kinetics	EFA	E1	E2	E3	E4	E5	E6	E7	E8	E9
First order reaction	0.9785	0.9661	0.9458	0.9811	0.9766	0.9654	0.9827	0.9748	0.9399	0.9433
Korsmeyer Peppas	0.9661	0.9777	0.9719	0.9659	0.9724	0.9611	0.9614	0.9668	0.9548	0.9522
Zero Order	0.9809	0.9529	0.9079	0.9249	0.9323	0.9278	0.9286	0.929	0.8726	0.8746
Higuchi	0.9069	0.9662	0.9687	0.9867	0.9854	0.9857	0.9978	0.9902	0.9654	0.9704
Hixon Crowell	0.9796	0.9677	0.9378	0.969	0.9677	0.965	0.9822	0.9646	0.9233	0.9281

Batches	E1	E2	E3	E4	E5	E6	E7	E8	E9
% Drug Content	89.64	93.28	93.94	98.91	99.90	99.90	98.25	98.91	98.24