Computational and Experimental Insights in Design and Development of Aceclofenac Co-Crystals

 

Chetan Hasmukh Mehta1, Poojary Pooja Srinivas1, Anusha SB1, Kirollos Bahaa Fathy Mahany2, KB Koteshwara1, Usha Yogendra Nayak1*

1Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.

2Faculty of Pharmacy, Assiut University, Egypt.

*Corresponding Author E-mail: usha.nayak@manipal.edu

 

ABSTRACT:

The present study is aimed at the design and development of aceclofenac co-crystals. Co-crystallization is one of the important techniques which helps to enhance the aqueous solubility of drugs by modifying the crystal structure using incorporation of the co-former into the formulation.. In the present study, supramolecular synthon approach and computational grid scan methods were used for the co-former selection. The different co-formers such as oxalic acid (OA), succinic acid (SA), maleic acid (MA), and benzoic acid (BA) were used. Aceclofenac (ACF) co-crystals were prepared by solvent evaporation and dry grinding method. Based on the computational results and experimental saturation solubility studies, maleic acid was considered as the suitable co-former for the preparation. The solid-state characterization showed partial conversion of ACF crystallinity to the amorphization as evident from the decrease in peak intensity and the number of peaks. The co-crystals showed increased aqueous solubility of ACF and higher drug release in basic pH. All the characterization parameters proved the co-crystal formation and the in vitro release studies showed that the solubility enhancement of the ACF by preparing ACF-MA co-crystals. Thus, it can be concluded that co-crystallization is one of the novel method for improving the bioavailability of aceclofenac.

 

KEYWORDS: Aceclofenac; Co-crystals; Computational grid scan calculations; Dry grinding technique; Solvent evaporation method; Supramolecular synthon approach.

 

 


INTRODUCTION:

Oral route is the most widely used and patient-friendly route for drug administration as it provides advantages such as self-administration, cost-effective and safety. Various dosage forms such as tablets, capsules, syrups, suspension can be administered by the oral route, but oral route administration is associated with the erratic bioavailability. Drug absorption through oral route is affected by several physico-chemical factors of the drug such as aqueous solubility, stability, dissolution, pKa, stability, first-pass metabolism, thus hindering its efficacy.

 

As the oral route is the most compliant route of drug delivery thus a tremendous amount of research is conducted on strategies to improve oral absorption of drugs.

 

Drug dissolution is pre-requisite for absorption of drug which depends on the solubility of drugs in gastrointestinal fluids (GIF). Thus modification of solubility and dissolution becomes the area of interest for the improvement of oral absorption of the drug1,2.

 

One of the significant problem responsible for the low turnout in the development of new molecular entities is due to poor solubility and reduced permeability of the lead compounds. The challenge in formulating poorly water-soluble drugs can be expected to increase in the course of time due to the increasing trend of newly discovered chemical entities where lipophilic molecules are dominant. Low bioavailability and erratic absorption are major problems associated with poorly water-soluble drugs. When aqueous solubility is low, the absorption of the drug becomes low and non-robust.  To sustain the drug effectiveness, it is required to dissolve in the gut fluids and pass through the gut membranes to get exposed in bloodstream so that it exhibits the desired therapeutic effect. 

 

As solubility and dissolution are the rate-limiting step to oral absorption for Biopharmaceutical Classification System (BCS) Class II drugs, improvement of those properties is considered as key factor for improving their bioavailability3–8. To deal with these problems, various physical (micronization, crystal habit modification, solid dispersion) and chemical modification (micellar solubilization, hydrotrophy, co-solvency, co-crystallization, and formation of salt form) techniques are available for enhancing the solubility of drug9. Among these solubility enhancement techniques, co-crystals formation is a promising approach for enhancing the solubility of BCS Class II drugs approved by U.S. Food and Drug Administration (USFDA). This method has wider range of advantages which started from improvement of mechanical properties to the stability of the product. Using this process, any active pharmaceutical ingredient (API), ionizable groups, acidic and basic can be co-crystallized potentially. Co-crystals are the crystalline materials composed of two or more (drug, co-formers and other) molecules held together by non-covalent bonds within the same crystal lattice. Numerous methods available for the preparation of co-crystals such as dry and wet grinding also called as solid and solvent drop grinding respectively, solvent evaporation, solvent crystallization, sono-crystallization and hot melt extrusion10–13. In co-crystal preparation, the co-former selection is one of the important step which required a lot of time and the cost for performing all the experiments. Many novel approaches are available for the effective selection of the co-former for the co-crystals preparation which includes supramolecular synthon approach, Cambridge structural database, computational grid scan method (binding energy calculations) and Hansen solubility parameter14–21.

 

Aceclofenac (ACF) is a non-steroidal anti-inflammatory drug (NSAID) used for relieving the symptoms in disease conditions such as rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. They act by reducing pain, fever, and inflammation. ACF is a phenyl acetic acid derivative, which acts by mitigating anti-inflammatory and antipyretic property. It is one of the safest and widely used drug amongst all other NSAIDs, because of its lower GI undesirable effect. However, its poor aqueous solubility results in its limited bioavailability after oral administration. Hence, improving its solubility remains a significant aspect in improving its therapeutic efficacy22–24. Scientists have worked on improving the solubility of ACF by various approaches like solid dispersion25, cyclodextrin complexes26,27, chitosan nanoparticles22, nanocrystals24,28–30 and co-crystals31–34. ACF co-crystals were prepared using nicotinamide and nicotinic acid as co-former by solution crystallization and neat grinding method31. Goud et al. 2013, prepared the novel solid product of ACF by using slurry grinding method which is having higher solubility as compared to pure drug32. Chandel et al. 2011, prepared the paracetamol and aceclofenac co-crystals and characterized for the various evaluation parameters33.

 

In the present study an  attempts was made to screen the suitable co-former by the supramolecular synthon approach and the computational grid scan calculations. The preparation of co-crystals included two different methods such as solvent evaporation (SE) method and dry grinding (DG) method using ACF and four different co-formers such as succinic acid (SA), oxalic acid (OA), benzoic acid (BA) and maleic acid (MA). The obtained co-crystals were characterized and evaluated for various experimental parameters including in-vitro drug release.

 

MATERIALS AND METHODS:

Materials:

Aceclofenac was gifted by the Lupin Pharmaceuticals, Inc., Pune. Succinic acid and benzoic acid were purchased from the Himedia Laboratories Pvt. Ltd., Mumbai. Maleic acid and oxalic acid were purchased from the Sisco Research Laboratories Pvt. Ltd., Mumbai. Remaining all other chemicals used were of analytical or laboratory grade.

 

Methods:

Preparation of ACF Co-crystals:

Co-former Selection:

In the present study, supramolecular synthon approach and grid scan energy calculations were performed for the selection of co-former in the preparation of co-crystals1,20.

 

Supramolecular synthon approach involves the determination of hydrogen bond acceptors and donors which required for the formation for hydrogen bond formation between the drug and co-formers as it’s the prime requirement in co-crystal formation. Finally, the hydrogen bond acceptors and donors of the co-formers was matched with the drug hydrogen acceptors and donors which can be selected for further studies20.

 

Grid scan calculation was performed in Material Science Schrodinger module to select the potential co-former molecule for co-crystals formation which involves optimization of structure of drug and co-former molecules by using LigPrep tool (LigPrep, Schrodinger, LLC, New York) to obtain the geometry optimized most stable structures (with the lowest energy) at neutral pH (7.0±0.0). The grid scan calculation was performed by selecting the co-former molecule as probe and drug as a target molecule. After this. Jaguar optimization was performed for drug-co-former complex, drug and co-former individually which helps in finding the binding energy (Kcal/mol). The molecules which is having least gas phase energy was considered as the molecule of the interest and considered for the co-crystal formation19,20.

 

Co-crystals Preparation:

The co-crystals were prepared by two different methods, such as solvent evaporation and dry grinding method using the ACF as an active pharmaceutical ingredient and various co-formers in two different molar ratios (1:6 and 1:10). In SE method, the weighed quantity of ACF and the co-former was dissolved in methanol and transferred to the china dish covered with the perforated aluminium foil to evaporate the solvent and get the co-crystals. In DG method, the weighed drug and co-formers were transferred to the azite mortar and continuously triturated with a pestle for 45 min. to form the co-crystals. The formed co-crystals were stored in desiccator for further analysis1,35.

 

Evaluation and Characterization of ACF Co-crystals:

Saturation Solubility Studies:

Saturated solution of ACF and co-crystals were prepared in water and kept for shaking at maintained temperature (37°C), 150rpm for 72 h. The samples were filtered, and the supernatant was analyzed for analyzing the ACF concentration using UV-visible spectrophotometer (UV1601 PC, Shimadzu, Japan) at 268.8nm.

 

Percent Practical Yield:

The percentage yield of the prepared co-crystals was calculated using the given formula below;

Percent yield (%) = (Practical yield/Theoretical yield) *100

 

Drug Content:

10mg of co-crystals was dissolved in the 10mL methanol, sonicated and filtered using syringe filter (0.22µm). The filtrate were analyzed for presence of ACF using UV-visible spectrophotometer at 268.8nm.

 

Solid-State Characterization of ACF Co-Crystals

The solid-state characterization of ACF co-crystals were performed by using Fourier transform infra-red spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and atomic force microscopy (AFM).

 

In Vitro Drug Release Studies:

The release profile of pure ACF and optimized co-crystals (ACF-MA) were studied using United States Pharmacopeia (USP) dissolution apparatus type-1 (Basket type). Co-crystals containing 100mg equivalent of ACF was weighed and added to the basket covered with the muslin cloth and dissolution studies were carried out in different buffers at temperature 37±0.5°C and speed at 75rpm for 3h. 2mL of samples were withdrawn at various time intervals and analyzed using UV-Visible Spectrophotometer at 268.8nm.

 

RESULTS AND DISCUSSION:

Preparation of ACF Co-crystals:

Co-former Selection:

As we know, preparation of any formulation requires the API and excipients, which are considered as the heart of the formulation. In co-crystal preparation, co-formers are the heart of the formulation which was used as the excipient. Selection of suitable excipients is one of the major task in co-crystallization.

 

In the present study, supramolecular synthon approach and grid scan calculations were used for the selection of co-former in the preparation of co-crystals. ACF (target molecule) has two hydrogen bond donors and five hydrogen bond acceptors.  SA, MA and OA have two hydrogen bond donors and four hydrogen bond acceptors while only BA has one hydrogen bond donor and two hydrogen bond acceptors. Based on this information, there were more chances of the hydrogen bond formation between the ACF and SA, MA and OA while less chance with BA20. The structures of drug and co-formers and the formation of hydrogen bond formation using computational studies is shown in the Fig. 1.

 

Based on the obtained results, maleic acid was considered as the best molecule as it has shown the smallest free energy among others and also formed three hydrogen bonds with the ACF molecules which indicates the favorable interactions, higher binding affinity and greater binding stability of the complex as compared to the other co-former molecules 1. The results of grid scan calculations were given in the Table 1.  Thus, order of binding affinity of co-former molecules with ACF was given as ACF-MA > ACF-OA > ACF-SA > ACF-BA.

 

Co-crystals Preparation:

ACF co-crystals were successfully prepared and based on observations, DG method was found to be better as compared to SE method as this method used for generation of novel co-crystallize phases and also multiple components co-grinding in solid state helps in the formation of stable polymeric structure. This method also considered as the environment friendly as solvents are not required for the preparation. Thus on the basis of this advantage, DG method was most suitable for the preparation of co-crystals formation as compared to the SE method36.

 

Saturation Solubility Studies:

The saturation solubility study results showed that, the pure drug ACF having very less solubility (0.13mg/mL), while the solubility of various prepared co-crystals was high as shown in the Fig. 2. ACF co-crystals prepared using MA as co-former was showing better solubility as compared to other co-formers and the pure ACF (drug). In this, ACF-MA co-crystals prepared using DG method (1:6 and 1:10) was showing better solubility as compared to the SE technique of co-crystals formation. Thus, the MA was optimized as the suitable co-former for preparation of co-crystals. Increase in solubility of ACF by preparing the co-crystals may be due to the partial amorphization of the ACF when increasing the concentration of co-former and also it indicates the decreasing in crystallinity by reducing the number of peaks and the peak intensity21,32.

 

Practical Yield and Drug Content:

The percent practical yield of the prepared ACF co-crystals using DG method and SE method were found between 87.18±1.17% to 95.98±1.29%. The drug content which was found between 85.95±0.49% to 92.8±1.13%. 

 

Solid State Characterizations:

DSC:

DSC was performed to check the thermal behavior of the pure ACF (drug), co-former (MA) and ACF-MA co-crystals. The strong endothermic peak was showed by ACF and MA at 155.5ºC and 144.79ºC in the DSC graph. The DSC graph of the co-crystals obtained from DG method exhibited a sharp endothermic peak at 142.73ºC and 149.8ºC (for 1:6 ratio) and 142.22ºC and 150.38ºC (for 1:10 ratio) whereas the DSC graph of the co-crystals obtained from SE method exhibited a sharp endothermic peak at 142.0ºC and 149.66ºC (for 1:6 ratio) and 140.82ºC and 148.22ºC (for 1:10 ratio). The slight decrease in the melting point of ACF-MA co-crystals or broadening of the two compounds peak (ACF and MA in co-crystals) in comparison to the ACF and MA alone might be due to formation of the novel solid     compound 21,31. The DSC curves for ACF, MA and co-crystals prepared by different methods and ratios were shown in the Fig. 3.     

 

 

FTIR:

The FTIR spectra of pure ACF and prepared co-crystals by two methods (DG and SE) and two different ratios (1:6 and 1:10) were analyzed and the results are shown in the Fig. 4. The pure ACF showed main functional bands at 1251.84 cm-1 represents C-N secondary amine stretching vibration, 1719.6 cm-1 C=O ester carbonyl group stretching vibration, 2933.83 cm-1 represents N-H stretching vibration and 3317.81 cm-1 represents -OH group of -COOH stretching vibrations. From the results, the main and major pure ACF peaks at 1251.84, 1719.6, 2933.83 and 3317.81 cm-1 appeared clearly in all the prepared co-crystals with the peak broadening which indicates the formation of hydrogen bond formation (intermolecular) and thus the co-crystal formation 31,37.

 

XRD:

The XRD pattern for the pure ACF and obtained co-crystals with two different ratios (1:6 and 1:10) and methods (DG and SE) were shown in Fig. 5. The crystalline nature of the ACF co-crystals was confirmed by using XRD pattern analysis and by comparing with the XRD pattern of the pure ACF. Pure drug ACF showed sharp intense diffractograms peaks at 18.5, 22.1, 24.4 and 25.8 degrees. The co-crystals prepared using dry grinding and solvent evaporation of 1:6 ratio exhibited sharp intense diffractograms at 17.4, 22.2, 25.8 and 27.9 degrees and 22.1, 22.7, 26.02 and 28.4 degrees, respectively. Whereas co-crystals prepared using dry grinding and solvent evaporation of 1:10 ratio showed sharp intense diffractograms at 17.1, 22.1, 25.5 and 27.7 degrees and 26.2, 27.8, 28.1 and 28.5 degrees, respectively. Co-crystals obtained with DG method shown decrease in the peak number as well as the intensity when compared to the pure ACF which is the main sign of partial amorphization of the drug during co-grinding process 21 while the co-crystals obtained with the SE method shown the crystalline nature which indicates the stable co-crystal formation. The co-crystal formation can be indicated by the incurring of the various physical or chemical bonding between the drug and co-formers which leads to transformation in the structure of crystal lattice followed by the pattern of crystallization 38,39.

 

AFM:

Based on these studies, it was clear that the co-crystals formed were in crystalline shape and the 2D and 3D images are shown in Fig. 6.


Table 1. Grid scan calculation results

ACF Co-former Complex

Gas phase energy

Interaction energy (Hartree)

Binding energy (Kcal/Mol)

No. of H-Bonds formed

Ranking

Complex value

ACF alone

Co-former alone

ACF-SA

-2351.014679

-1893.903845

-457.104615

- 0.006219

-3.8912283

3

3

ACF-MA

-2349.859828

-1893.904299

-455.872857

- 0.082672

-51.7278704

3

1

ACF-BA

-2313.416315

-1893.364921

-420.378763

0.327369

204.8347833

2

4

ACF-OA

-2272.357819

-1893.905959

-378.435534

- 0.01633

-10.2151782

2

2

*ACF – Aceclofenac, SA – Succinic acid, MA – Maleic acid, BA – Benzoic acid, OA – Oxalic acid

 

 

Fig. 1. Pure drug, ACF, various co-formers and hydrogen bond (H-bond) interaction formed between the ACF and co-former (H-Bonds – Yellow dotted lines)

 


Fig. 2. Saturation solubility studies of co-crystals

 

In Vitro Drug Release Studies:

In vitro drug release studies were performed to check the dissolution behavior of the pure ACF and ACF co-crystals. In vitro drug release profile of pure drug (PD, ACF) and prepared co-crystals (DG and SE method in the ratio of 1:6 and 1:10) was performed and the results were shown in the Fig. 7. The ACF-MA co-crystals showed higher dissolution in comparison to the pure ACF in basic dissolution media as compared to acidic dissolution media due to changes in the crystal habit, crystallinity pattern, shape and size of the ACF thus it helps in solubility enhancement of ACF in the dissolution medium1. Based on the solid state characterization results mainly XRD, it can be concluded that as the co-former concentration is increasing, there is reduction of peak intensity as well the peak number when compared with the pure drug and also it indicates the partial amorphization of drug in co-crystals which also indicates the solubility enhancement of drug in dissolution medium21,34.

 

 

Fig. 3. DSC graphs of ACF, MA and Co-crystals prepared by DG and SE method in two different ratios (1:6 and 1:10)

 

Fig. 4. FTIR characteristics peaks of pure ACF and different obtained co-crystals

 

Fig. 5. XRD of pure ACF and different obtained

 

Fig. 6. 3D images of co-crystals (DG – 1:6)

 

Fig. 7. In vitro drug release profile of pure drug (PD, ACF) and prepared co-crystals

 

CONCLUSION:

Nowadays, many drugs are coming under the BCS class II category which indicates the low solubility and the higher permeability. Hence different techniques are required to enhance the solubility of the poorly soluble drugs which are coming under BCS class II. Although, various techniques are available for the solubility enhancement, co-crystallization has certain better advantages as compared to other techniques used for the solubility enhancement. In the present study, co-formers were selected on the basis of supramolecular synthon approach and grid scan calculations for the co-crystal preparation and on the basis of the saturation solubility studies, one co-crystal formulation (ACF-MA) was optimized. The saturation solubility method also showed that dry grinding method was more suitable for the solubility enhancement as compared to the solvent evaporation method. The optimized co-crystals were used for solid state characterization (FTIR, DSC, XRD and AFM) as well as the other evaluation parameters (drug content, in vitro drug release studies). All the characterization parameters proved the co-crystal formation and the in vitro release studies showed that the solubility enhancement of the ACF by preparing ACF-MA co-crystals.

 

ABBREVIATIONS:

ACF – Aceclofenac

SA – Succinic Acid

MA – Maleic Acid

OA – Oxalic Acid

BA – Benzoic Acid

GIF -- Gastrointestinal Fluids

BCS -- Biopharmaceutical Classification System

API -- Active Pharmaceutical Ingredient

USFDA - U.S. Food and Drug Administration

NSAIDs -- Non-Steroidal Anti-Inflammatory Drugs

FTIR -- Fourier Transform Infra-red Spectroscopy.

DSC -- Differential Scanning Calorimetry

XRD -- Powder X-ray Diffraction

AFM -- Atomic Force Microscopy

SE -- Solvent Evaporation

DG -- Dry Grinding

USP - United States Pharmacopeia

 

ACKNOWLEDGEMENT:

Authors are thankful to Lupin Pharmaceuticals, Inc., Pune for providing the gift sample of drug. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors are thankful to Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal for providing the instrumental and infrastructure facilities for carrying out the research work. 

 

CONFLICT OF INTEREST:

There is no conflict of interest.

 

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Received on 27.01.2021           Modified on 17.07.2021

Accepted on 02.11.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(8):3709-3716.

DOI: 10.52711/0974-360X.2022.00622