INTRODUCTION:

Active Pharmaceutical Ingredients (APIs) exist in various solid-state forms such as polymorphs, solvates, salts, co-crystals, and amorphous solids. Each of these forms possesses distinct physicochemical characteristics that significantly influence the bioavailability, stability of pharmaceutical products^1,2. A major challenge in modern drug development is the high prevalence of poorly water soluble drug candidates. These compounds are frequently classified under the Biopharmaceutical Classification System (BCS) as Class II (low solubility, high permeability) or Class IV (low solubility, low permeability), where the rate-limiting step for absorption is often drug dissolution in the gastrointestinal tract^3-6. Several formulation strategies have been employed to improve the solubility of poorly water-soluble drugs, including chemical modification, solid dispersion, complexation, co-solvency, micellar solubilisation, hydrotropy, and micronization^6-9. While these methods have achieved varying degrees of success, limitations such as physical instability, scalability issues, and regulatory complexity necessitate the exploration of alternative approaches.

Pharmaceutical co-crystallization has emerged as a promising strategy to address solubility challenges. G.R. Desiraju defines crystal engineering as “the comprehension of intermolecular interactions relative to crystal packing and application of such comprehension in the design of new solids with desired physical and chemical properties”^10-13. Co-crystals are crystalline materials composed of an API and a pharmaceutically acceptable co-former in a definite stoichiometric ratio, held together by non-covalent interactions such as hydrogen bonding, van der Waals forces, or π–π stacking^14-16. These systems offer distinct advantages, including enhanced solubility, improved stability, and retention of the API's chemical integrity. Nitrendipine, a dihydropyridine calcium channel blocker, exemplifies a BCS Class II drug with extremely poor aqueous solubility (approximately 2.0µg/mL at 37°C) and low oral bioavailability (10–20%), primarily due to dissolution-limited absorption^17-19. Enhancing its solubility is therefore crucial for improving therapeutic efficacy and reducing interindividual variability. In this study, co-crystallization is explored as a strategy to enhance the solubility of Nitrendipine. Gallic acid, a Generally Recognized as Safe (GRAS) compound with multiple hydrogen bond donor and acceptor sites, is selected as a suitable co-former to develop Nitrendipine co-crystals. The aim of the present study was to improve the dissolution behavior of Nitrendipine through co-crystal formation, thereby potentially enhancing its oral bioavailability.

METHODS AND MATERIALS:

Materials:

Nitrendipine was procured from Concept Pharmaceuticals Ltd. Mumbai. Gallic acid and methanol (analytical grade) were purchased from Loba Chemie Pvt. Ltd, Mumbai, Maharashtra, India. All other chemicals used for analysis were of analytical grades.

In silico studies:

Suitability of Gallic acid as a coformer:

The suitability of Gallic acid as a coformer for Nitrendipine co-crystal formation was evaluated using COSMOquick software, which predicts co-crystallization potential based on quantum chemical and thermodynamic descriptors. After inputting the SMILES structures of both compounds, parameters such as excess enthalpy (H_ex), hydrogen bond enthalpy (H_hb), Gibbs free energy of mixing (G_mix), fit function (f_fit), similarity, fragmentation quality (frag_quality), and overall coformer ranking were generated. Negative values of H_ex and G_mix indicated favorable interactions and spontaneous mixing, while a high H_hb value suggested strong hydrogen bonding potential. The f_fit and similarity scores reflected good molecular complementarity.

To validate the software's predictions, previously reported coformers of Nitrendipine were analysed, yielding results consistent with experimental data. Structural properties such as rotatable bonds, ring bonds, and conjugated systems were also assessed to evaluate molecular flexibility and packing potential. Overall, the COSMOquick analysis supported Gallic acid as a promising coformer due to its favorable thermodynamic profile, interaction potential, and structural compatibility with Nitrendipine.

Preparation and evaluation of Nitrendipine cocrystals:

The stoichiometric ratio for co-crystallization and eutectic mixture formation can be predicted by analysing the melting behavior of drug–coformer combinations. To investigate this, binary physical mixtures of Nitrendipine and Gallic acid were prepared at various molar ratios (0.1 to 0.9 mole fraction of Nitrendipine) in increments of 0.1. Each mixture was thoroughly blended using manual solid-state grinding in a mortar and pestle for 10min. to ensure homogeneity. The thermal behavior of the pure components and physical mixtures was studied using Differential Scanning Calorimetry and melting points were also determined via the capillary method.

The presence of new thermal events or the disappearance of individual component melting points was used as an indicator of potential cocrystals formation. Mixtures that showed single, sharp endothermic peaks distinct from those of the pure components were considered probable cocrystals candidates. Based on the DSC results, selected ratios were subjected to solid-state grinding for 10min. to promote co-crystallization. These ground mixtures were then suspended in methanol and processed using a rotary evaporator (Heidolph, Germany) at 50°C and 100 RPM until complete solvent removal. The resulting solid products were collected for further characterization to confirm cocrystals formation^20,21.

Saturation solubility:

A saturation solubility study of Nitrendipine, Gallic acid, their physical mixtures, and solvent-evaporated co-crystal candidates was carried out using the phase solubility method. Accurately weighed quantities of 50.0 ±0.5mg of each sample were added separately into 10 mL of three different solvents: distilled water, methanol, and 0.1N HCL, in tightly stoppered conical flasks. These solvents were selected to represent a range of polarities and physiological pH conditions: distilled water for neutral media, methanol for organic solubility enhancement, and 0.1 N HCL to mimic gastric pH.

The flasks were agitated at 37±0.5°C in an orbital shaker for 72h to ensure saturation and establish equilibrium. After incubation, the samples were centrifuged at 2000 rpm for 15min. to remove undissolved material. The supernatant was filtered using Whatman filter paper no. 45, and the concentration of Nitrendipine in the filtrate was determined spectrophotometrically using a UV-Visible spectrophotometer (Shimadzu UV-1800, Japan) at a wavelength of 236nm. The λmax of 236nm was previously determined by scanning a standard Nitrendipine solution in the range of 200-400nm. Quantification was performed using a calibration curve constructed from standard solutions of Nitrendipine in the corresponding solvents, with concentrations ranging from 2 to 20µg/mL. The curve demonstrated excellent linearity (R²>0.998), confirming its suitability for solubility analysis^22.

Differential scanning calorimetry (DSC):

Differential Scanning Calorimetry (DSC) analysis was conducted to assess the thermal behavior of Nitrendipine, Gallic acid, their physical mixtures (ranging from 0.1 to 0.9mol fraction of Nitrendipine), and the solvent-evaporated mixtures. Approximately 3-5 mg of each accurately weighed sample was sealed in an aluminium pan and analysed using a DSC instrument (Lab METTLER) under a nitrogen atmosphere. The thermograms were recorded over a temperature range of 25°C to 300°C, with a constant heating rate of 10°C/min.

Comparison between the thermograms of the physical mixtures and solvent-evaporated products allowed further confirmation of co-crystallization, as solvent-evaporated samples exhibiting new thermal events or altered peak patterns provided strong evidence of new solid-state forms.

X-ray diffraction studies:

Powder X-ray diffraction (PXRD) patterns of Nitrendipine, Gallic acid, and the prepared cocrystals were recorded using a D2 Phaser Bruker diffractometer equipped with a Cu Kα radiation source (λ = 1.5418 Å) and a beta filter. Diffraction data were collected over a 2θ range of 5° to 50° with a step size of 0.02°, under ambient conditions. For comparison, simulated PXRD patterns of pure Nitrendipine and Gallic acid were generated using crystallographic data obtained from the literature. These simulations were performed using Mercury software (version 4.1.3, free version) based on their respective CIF files.

The experimental PXRD patterns of the cocrystals were compared to the simulated patterns of the individual components to assess changes in crystallinity and phase identity. The degree of match between experimental and simulated patterns was evaluated qualitatively by peak position and intensity differences, confirming successful co-crystallization²³.

FTIR spectroscopy:

Fourier-transform infrared (FTIR) spectroscopy was employed to investigate possible intermolecular interactions between Nitrendipine and Gallic acid, as well as to confirm cocrystals formation. FTIR spectra of pure Nitrendipine, Gallic acid, and the solvent-evaporated mixture were recorded using a Jasco 4700 FTIR spectrophotometer. Each sample was prepared by the conventional KBr pellet method: approximately 1–2 mg of finely ground sample was mixed with 100 mg of dry potassium bromide, compressed into a transparent pellet using a hydraulic press, and scanned over a wavenumber range of 4000–400 cm⁻¹ at a resolution of 2 cm⁻¹.

In vitro dissolution study:

In vitro dissolution study was performed to compare the dissolution behavior of pure Nitrendipine, its physical mixture with Gallic acid, and the Nitrendipine–Gallic acid cocrystals prepared via solvent evaporation. Each sample, equivalent to 20mg of Nitrendipine, was introduced into 1000mL of phosphate buffer (pH 7.4), prepared using 0.2M monobasic potassium phosphate and 0.2M sodium hydroxide, selected to simulate intestinal pH conditions. The dissolution medium was maintained at 37±0.5°C and agitated at 100 rpm in an orbital shaker.

At specified intervals of 5, 10, 15, 30, 45, 60, and 120 mins. 1 mL aliquots were withdrawn using a syringe fitted with a 0.45 µm membrane filter and immediately replaced with an equal volume of pre-warmed fresh buffer to maintain volume and sink conditions. The withdrawn samples were appropriately diluted and analysed at a wavelength of 237 nm using a UV-Visible spectrophotometer (Shimadzu UV-1800, Japan).

A standard calibration curve of Nitrendipine in phosphate buffer was used for quantification (R² > 0.998). Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test, with p < 0.05 considered statistically significant.

RESULT AND DISCUSSION:

In silico studies:

Suitability of gallic acid as a coformer:

The suitability of gallic acid as a coformer for the co-crystallization of nitrendipine was assessed using COSMO quick software, which predicts cocrystals formation based on thermodynamic and structural parameters derived from quantum chemical calculations. The excess enthalpy (H_ex = 2.05) and hydrogen bonding enthalpy (H_hb = 2.71) were calculated, where lower values are indicative of more stable interactions between the drug and coformer. These values suggest favourable non-covalent interactions, particularly hydrogen bonding, that support the likelihood of cocrystals formation.

The mixing free energy (G_mix) was determined to be 1.12, and the flexibility-fit factor (f_fit) was 3.40. A positive G_mix value close to zero suggests marginal but thermodynamically permissible cocrystals formation, while a moderate f_fit value reflects acceptable molecular flexibility and compatibility of the components. Together, these parameters support the feasibility of stable cocrystals formation between nitrendipine and gallic acid.

The predicted structural similarity score between nitrendipine and gallic acid was 9, which is the highest on a normalized scale used by COSMOquick (0-10), indicating excellent complementary molecular features such as hydrogen bond donors/acceptors and shape compatibility. The fragmentation quality (frag_quality = 0) and coformer rank (Rank = 1) further confirmed gallic acid as the top-ranked coformer for nitrendipine among the tested candidates.

Additionally, the software predicted molecular features contributing to the interaction, including 5 rotatable bonds, 6 ring bonds, 7 conjugated bonds, and 4 internal bonds for the nitrendipine–gallic acid system. These parameters fall within the range typically associated with successful cocrystals formation, supporting gallic acid suitability as a coformer shown in table 1 and ranking wise prediction of coformer for formulation of cocrystals depicted in fig.1.

Table 1: In silico cocrystals screening data for nitrendipine and coformers by COSMOquick software.

Sr. no	Coformer	API	Status	Rotatable bonds	G_mix [kcal/mol]	H_hb [kcal/mol]	f_fit	coformer_ ranking	H_ex [kcal/ mol]
1.	Benzoic Acid	RD0JBY8TMUEU	Unknown	2.0	-0.60118443	-0.52202	4.011545	4.0	-0.580255
2.	Ascorbic Acid	RD0JBY8TMUEU	Unknown	6.0	-0.41174943	-0.572175	5.950595	7.0	-0.682005
3.	Polyvinylpolypyrrolidone	RD0JBY8TMUEU	Unknown	1.0	-0.56122443	-0.169805	3.76784	2.0	-0.31376
4.	Gallic Acid	RD0JBY8TMUEU	Unknown	5.0	-1.12011443	-2.05242	3.403275	1.0	-2.719125
5.	Caffeine	RD0JBY8TMUEU	Unknown	0.0	-0.45911443	-0.089815	3.97684	3.0	-0.10476
6.	Thiourea	RD0JBY8TMUEU	Unknown	2.0	-0.05308443	-0.168685	4.405925	5.0	-0.185875
7.	1,2-Ethanediol	RD0JBY8TMUEU	Unknown	3.0	-0.02891943	0.407985	5.56717	6.0	0.46517
8.	Diethylene Glycol	RD0JBY8TMUEU	Unknown	6.0	-0.39003943	0.173305	6.73295	8.0	0.10035
9.	Mrrio9tx48nn	RD0JBY8TMUEU	Unknown	18.0	-0.27501443	-0.001355	12.985915	9.0	0.230915

Figure 1: Ranking wise prediction of coformer for formulation of cocrystals.

Preparation and evaluation of Nitrendipine cocrystals:

To investigate the possibility of cocrystals formation between nitrendipine and gallic acid, nine physical mixtures were prepared using stoichiometric ratios corresponding to molar fractions of gallic acid ranging from 0.1 to 0.9 M. Each mixture was prepared by accurately weighing the drug and coformer, followed by thorough grinding using a mortar and pestle for 10 min. to ensure uniform mixing.

The thermal behavior of the individual components and the physical mixtures was examined using Differential Scanning Calorimetry (DSC) and melting point determination by the capillary method. Nitrendipine exhibited a sharp melting point at 158 °C, while gallic acid melted at 260 °C. The melting points of the physical mixtures varied depending on the composition, and a deviation from the melting behavior of the pure components was used as an indicator of possible cocrystals formation.

Among the mixtures, the formulation containing a 0.2 M molar fraction of gallic acid showed a distinct melting behavior- characterized by the appearance of a new thermal event or the disappearance of the individual melting endotherms- suggesting the formation of a new solid phase. This observation was used as a basis to select the 0.2 M ratio for further solvent evaporation-based co-crystallization. The results indicate that although multiple ratios showed potential deviations, the 0.2 M mixture demonstrated the most promising thermal behavior consistent with cocrystals formation and found possibilities with all the stoichiometric ratios presented in table 2. We Then we prepared cocrystals of all ratios by using a method solvent evaporation. We find a clear cocrystals with the stoichiometric ratios, with drug concentration of 0.2 M. These were selected for further study.

Table 2: Melting behaviour of all stoichiometric ratios.

Sr. No.	Concentration of Nitrendipine (Molar)	Concentration of Gallic acid (Molar)	Melting point of Physical mixture (Celsius)
1	0.1	0.9	2200
2	0.2	0.8	1800
3	0.3	0.7	2250
4	0.4	0.6	2100
5	0.5	0.5	2000
6	0.6	0.4	2200
7	0.7	0.3	2050
8	0.8	0.2	2000
9	0.9	0.1	1850

Saturation solubility:

Saturation solubility of pure nitrendipine and its cocrystals with gallic acid was evaluated in three different solvents: methanol, 0.1 N hydrochloric acid (HCL), and distilled water. The study was performed using the shake-flask method. Accurately weighed excess amounts (approximately 50mg) of nitrendipine or its cocrystals were added to 10mL of each solvent in separate conical flasks. The flasks were sealed and agitated at 37±0.5°C in an orbital shaker for 72h to ensure equilibrium solubilisation.

After incubation, the mixtures were centrifuged at 2000 rpm for 15mins, and the supernatants were filtered using Whatman No. 45 filter paper. The filtrates were analysed using a UV-Visible spectrophotometer (Shimadzu UV-1800) at λmax 236 nm. A calibration curve was constructed in each solvent to determine drug concentration.

The solubility of nitrendipine and its cocrystals in methanol was found to be 8.32mg/mL and 12.35 mg/mL, respectively. In 0.1 N HCL, the solubility was 6.10mg/mL for nitrendipine and 9.00mg/mL for the cocrystals. In distilled water, solubility was 4.97mg/mL and 7.69mg/mL, respectively. These results clearly indicate a significant enhancement in solubility across all solvents due to cocrystals formation.

Differential scanning calorimetry:

The thermal behavior of nitrendipine, gallic acid, and their physical mixtures at various molar ratios were analyzed using Differential Scanning Calorimetry. The DSC thermogram of pure nitrendipine exhibited a sharp endothermic peak at 161.38°C, corresponding to its melting point, while gallic acid showed a distinct endothermic peak at 259.32°C. Among the prepared physical mixtures, the 0.5 and 0.9mol fractions of nitrendipine exhibited broad and lower melting endotherms at 156.07°C and 157.38°C, respectively depicted in Fig. 2 and Fig. 3. These peaks were significantly lower than the melting points of the individual components and are characteristic of eutectic mixtures, indicating physical mixing without the formation of a new solid phase.

In contrast, the physical mixture with a 0.2mol fraction of nitrendipine displayed a sharp endothermic peak at 244.31 °C, which did not correspond to the melting point of either nitrendipine or gallic acid shown in Fig. 4. This new thermal event suggests the formation of a distinct crystalline phase, consistent with cocrystals formation. The presence of a single sharp peak, significantly shifted from the melting points of the pure components, is a key indicator of successful co-crystallization. These findings support the selection of the 0.2 mol fraction for further solid-state characterization, as it most likely represents a stable cocrystals rather than a eutectic system.

Figure 2: DSC thermogram of overlay of Nitrendipine, Gallic acid and 0.5 M ratio.

Figure 3: DSC thermogram of overlay of Nitrendipine, Gallic acid, and 0.9 M ratio.

Figure 4: DSC thermogram of overlay of Nitrendipine, Gallic acid and 0.2 M ratio.

X-ray diffraction studies:

Powder X-ray diffraction (PXRD) was employed to investigate the solid-state structure of pure nitrendipine, gallic acid, and their cocrystals. Data was collected using a Bruker D2 Phaser diffractometer equipped with a Cu Kα radiation source (λ = 1.5418 Å), operating at 30 kV and 10mA. Scans were recorded over a 2θ range of 5° to 50° with a step size of 0.02° and a scan rate of 1s per step. The PXRD pattern of nitrendipine displayed intense, sharp peaks predominantly at low 2θ values (notably around 10° and 20°), confirming its crystalline nature. Gallic acid also exhibited a distinct crystalline profile, with major diffraction peaks observed around 17° and 25°, indicating well-ordered molecular packing shown in Fig. 5. Simulated XRD patterns for both pure compounds were generated using Mercury 4.1.3 software based on crystallographic data reported in the literature, serving as references for comparison.

The PXRD pattern of the nitrendipine–gallic acid cocrystals exhibited a new set of diffraction peaks that were distinct from those of either parent compound, with the disappearance of characteristic peaks of both nitrendipine and gallic acid. This suggests the formation of a new crystalline phase. For instance, reflections at 10° and 20° (nitrendipine) and 17° and 25° (gallic acid) were absent in the cocrystals pattern, while new peaks emerged at intermediate positions, indicating successful co-crystallization and the generation of a unique solid-state structure. Furthermore, a low-intensity diffuse background pattern was observed in the cocrystals diffractogram, possibly indicating the presence of minor amorphous content or poorly ordered crystalline regions. These observations were consistent with DSC results, further supporting the formation of a cocrystals rather than a eutectic mixture or simple physical blend. While the exact crystals system of the nitrendipine-gallic acid cocrystals could not be assigned without single-crystal data, the appearance of new PXRD peaks and the loss of parent compound reflections strongly confirm the creation of a new solid form.

Figure 5: XRD of Nitrendipine, Gallic acid and cocrystals.

FTIR spectroscopy study:

FTIR spectroscopy study was employed to investigate the intermolecular interactions between nitrendipine and gallic acid in the prepared cocrystals. The spectras were recorded using a Jasco FTIR-4700 spectrophotometer in the range of 4000–400 cm⁻¹ with a resolution of 2 cm⁻¹. Samples were prepared using the KBr pellet method to ensure proper dispersion. The FTIR spectrum of pure nitrendipine exhibited a sharp peak around 1700 cm⁻¹ corresponding to C=O stretching, indicative of the carbonyl group. Additionally, peaks observed between 1600–1620 cm⁻¹ were attributed to aromatic ring vibrations and dihydropyridine ring stretching. Strong absorptions in the region of 1500–1350 cm⁻¹ confirmed the presence of nitro functional groups. Gallic acid, on the other hand, showed a broad O–H stretching band around 3368 and 3366 cm⁻¹, indicating extensive hydrogen bonding among hydroxyl groups. A sharp peak at 2538 cm⁻¹ was attributed to hydrogen-bonded –OH stretching of the carboxylic acid group. The characteristic C=C stretching of the aromatic ring appeared between 1610–1450 cm⁻¹, confirming the polyphenolic structure of gallic acid. In the FTIR spectrum of the nitrendipine–gallic acid cocrystals, several notable changes were observed. The carbonyl stretching peak of nitrendipine shifted slightly to 1692 cm⁻¹, suggesting the formation of hydrogen bonds with the hydroxyl groups of gallic acid. Similarly, the broad O–H stretching band of gallic acid shifted to a lower wavenumber (~3350 cm⁻¹) and became broader, further indicating strong hydrogen bonding interactions in the cocrystals. Minor shifts in the aromatic and nitro regions were also evident, pointing to changes in the electronic environment around the functional groups. These spectral modifications confirm the formation of non-covalent interactions, particularly hydrogen bonding, between nitrendipine and gallic acid. The observed peak shifts and broadening in the FTIR spectrum of the cocrystals support the successful formation of a new solid-state form with distinct physicochemical properties compared to the individual components shown in Fig. 6.

Figure 6: FTIR of Nitrendipine, Gallic acid and Cocrystals

In vitro dissolution study:

An in vitro dissolution study was conducted to compare the drug release profiles of pure nitrendipine and its cocrystals with gallic acid. The study was performed using an orbital shaker dissolution apparatus with 1L of phosphate buffer solution at pH 7.4 as the dissolution medium. The temperature was maintained at 37 ± 0.5 °C, and the shaking speed was set at 100 rpm to simulate gastrointestinal motility. An equivalent dose of 20 mg of nitrendipine was used for each formulation. Samples of 1 mL were withdrawn at predetermined intervals (1, 5, 10, 15, 30, 45, 60, and 120 mins) and immediately replaced with an equal volume of fresh buffer to maintain sink conditions. The withdrawn samples were filtered, appropriately diluted, and analyzed using a UV-visible spectrophotometer (Shimadzu UV-1800) at λmax 237 nm.

The dissolution rate of the cocrystals was significantly enhanced compared to that of the pure drug. At 1 and 5 mins, the drug release from the cocrystals was approximately 7% and 11%, respectively, whereas pure nitrendipine showed only 4% and 7% release shown in Fig. 7. The improvement became more prominent with time: at 60 mins. the cocrystals released around 58% of the drug, while the pure drug reached only about 30%. By 120 mins., the cumulative drug release from the cocrystals was approximately 74%, compared to 35% from pure nitrendipine. This substantial enhancement in dissolution indicates a marked improvement in solubility due to co-crystallization with gallic acid. The increased surface area, improved wettability, and altered crystal packing of the cocrystals likely contribute to this enhanced dissolution. A statistical comparison using one-way ANOVA followed by Tukey's post hoc test (p < 0.05) confirmed that the differences in dissolution rates between the cocrystals and the pure drug were statistically significant at all time points. These findings clearly support the potential of co-crystallization as a strategy for improving the dissolution and bioavailability of poorly soluble drugs like nitrendipine.

Figure 7: In vitro dissolution study of Nitrendipine and Cocrystals

CONCLUSION:

This study successfully demonstrated the potential of gallic acid as a coformer for enhancing the solubility and dissolution of nitrendipine through co-crystallization. COSMOquick software predicted gallic acid as the most suitable coformer, with favorable interaction parameters including a low excess enthalpy (H_ex = 2.05), hydrogen bonding enthalpy (H_hb = 2.71), and a high fit score (f_fit = 3.40), indicating a strong propensity for cocrystals formation. Among various stoichiometric ratios explored, the 0.2 mole fraction of nitrendipine yielded a distinct melting point at 244.31 °C in DSC thermograms, confirming cocrystals formation. In contrast, eutectic behavior was observed at 0.5 and 0.9 mole ratios, with endothermic peaks near the melting point of the pure drug. PXRD patterns of the cocrystals exhibited the disappearance of key peaks from the parent compounds and the emergence of new diffraction peaks, indicating the formation of a new crystalline phase. FTIR analysis revealed peak shifts in functional groups (notably the carbonyl and hydroxyl stretch), further supporting the formation of intermolecular hydrogen bonds between nitrendipine and gallic acid in the cocrystals. Solubility studies demonstrated substantial improvements in all tested media. In methanol, the solubility of nitrendipine increased from 8.32 mg/mL to 12.35 mg/mL (an improvement of 48.4%). In 0.1 N HCL and distilled water, enhancements of 47.5% and 54.7% were observed, respectively. The in vitro dissolution study revealed that at 120 mins, the cocrystals released 74% of the drug compared to only 35% from pure nitrendipine- a statistically significant difference (p < 0.05), confirming enhanced dissolution performance. The improved solubility and dissolution profile was attributed to changes in the crystal lattice structure and the formation of hydrogen bonds, which reduce lattice energy and enhance wettability. Additionally, long-term stability and scalability of the cocrystals should be assessed to determine their suitability for pharmaceutical development. In conclusion, gallic acid is a highly effective coformer for nitrendipine, capable of forming a stable and soluble cocrystals at an optimal 0.2 mole ratio. This approach offers a viable strategy to overcome solubility limitations of BCS Class II drugs like nitrendipine, potentially improving therapeutic efficacy and patient compliance.

ACKNOWLEDGEMENTS:

I would like to express my gratitude to my mentor, Dr. Anilkumar J. Shinde, Associate Professor in the Pharmaceutics Department at Bharati Vidyapeeth College of Pharmacy in Kolhapur, for his invaluable time, superb leadership, careful supervision, encouragement, and constant motivation.

CONFLICT OF INTEREST:

The authors declared no conflict of interest.

AUTHOR CONTRIBUTIONS:

The experiment was planned, carried out, and data was evaluated by the author, who also wrote the manuscript. Each author contributed equally to the completion of this study.

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Received on 12.07.2025 Revised on 08.11.2025

Accepted on 03.01.2026 Published on 01.07.2026

Available online from July 04, 2026

Research J. Pharmacy and Technology. 2026;19(7):3295-3303.

DOI: 10.52711/0974-360X.2026.00469

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