Development and characterization of Irbesartan Co-Crystals

 

Akhil Nair, Harini R, Melissa P, Krupali Shah, Usha Y Nayak*, Mahalaxmi R,

Vamshi Krishna T

Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India–576104

 

ABSTRACT:

The aim of the work was to prepare co-crystals of irbesartan (IBS), a BCS Class II drug to enhance its aqueous solubility and bioavailability. The solvent evaporation method was used to prepare co-crystals by using different co-formers and varying the drug to co-former molar ratios. Succinic acid and benzoic acid co-crystals were formed with good physicochemical properties. The solid-state characterization of co-crystals was studied by FTIR, DSC, and XRD. The co-crystals were evaluated for the saturation solubility and dissolution studies. There was a 2-fold increase in the aqueous solubility and 4-8 fold increase in dissolution rate of co-crystals. Solid state characterizations indicated there was no change in the chemical nature of the co-crystals compared to pure drug. Presence of crystalline co-former induced crystallinity  to the developed co-crystals. Thus, developed co-crystals were found to be a suitable alternative to increase the solubility and dissolution rate of IBS.

 

 

 

INTRODUCTION:

The oral route of drug administration is most preferred route and commonly employed because of high patient compliance and cost-effectiveness. Oral dosage forms also have advantage of flexibility in the design and least sterility constraints with respect to manufacturing. However, the major hurdle with oral dosage form is the poor bioavailability of drugs with respect to low solubility and permeability¹.The rate of dissolution of the drug in gastrointestinal (GI) fluid depends on the solubility. Thus solubility and dissolution are interdependent. The low solubility of the drug can be increased by several methods. Micronization, nanonization, use of soluble carriers, complexation and solid dispersion technique, are some of the methods to improve the solubility of drugs.

 

 

Irbesartan (IBS), an antihypertensive drug belonging to the class angiotensin II receptor antagonist. It is available in the form of film coated tablet marketed by Bristol-Myers Squibb and Sanofi-Aventis. It is also available in combination with hydrochlorothiazide for additional antihypertensive effect. IBS belongs to BCS class II possessing low solubility and high permeability. It is practically insoluble in water and highly lipophilic drug. Poor water solubility is associated with poor dissolution characteristics; this may necessitate an increase in the dose of the drug. Solubility is the major concern for the majority of the drugs and is a rate-limiting factor for the absorption. Thus such drugs exhibit poor therapeutic activity due to poor bioavailability^2–4.

 

Many techniques have been attempted to enhance the solubility of IBS. Microcrystal technology was used, where the aqueous (non-solvent) phase was poured instantly to the methanolic IBS solution under magnetic stirring. This leads to super saturation of the drug, subsequent nucleation and crystal formation⁵.The solid dispersions were prepared by spray drying method using low viscosity grade HPMC wherein the crystalline form of IBS was converted to amorphous form. Due to the presence of surfactant and hydrophilicity of HPMC, solubility and stability of solid dispersion were increased⁶.Complexation technique was also attempted, usingγ-cyclodextrin. The release was found to increase with increasing γ-cyclodextrin concentration at both pH values⁷.

 

However, no attempts were made to formulate IBS into co-crystals. Co-crystals are crystalline materials composed of two or more different molecules, typically drug and co-crystal formers (‘coformers’), in the same crystal lattice. Pharmaceutical co-crystals have opened up opportunities for engineering solid-state forms beyond conventional solid-state forms of an active pharmaceutical ingredient (API), such as salts and polymorphs,” FDA explains. “Co-crystals can be tailored to enhance drug product bioavailability and stability and to enhance the processability of APIs during drug product manufacture ⁸. Thus in the present investigation, the effect of co-crystals on solubility enhancement of IBS was investigated.

 

The main objective of the present study was to develop co-crystals of IBS, which can enhance the solubility and provide immediate release of orally administered IBS by enhancing its dissolution in the aqueous contents of the GI tract. The increased solubility and permeability promotes the fast onset of action and maximum drug release within few minutes. Using co-crystallization technique, co-crystals of IBS were prepared using co-formers including benzoic acid, succinic acid, and maleic acid, by a solvent evaporation method. The structures of IBS and the co-formers used in the present work is shown in Fig. 1.

 

 

Fig.1 Structure of IBS and different co-formers

 

 

MATERIALSANDMETHODS:

Materials:

IBS was obtained from Lupin Pvt. Ltd., Pune as a gift sample. Benzoic acid, succinic acid, and maleic acid were procured from HiMedia Laboratories Pvt. Ltd, Mumbai. Other chemicals such as Methanol was from Labort Fine Chemicals Pvt. Ltd., Mumbai; Potassium Dihydrogen ortho Phosphate was from Spectrochem, Mumbai, di-Sodium Hydrogen Phosphate and Acetone were from Merck Chemicals, Mumbai, Sodium Hydroxide Pellet Purified was from HiMedia Laboratories Pvt. Ltd.

 

Preparation of co-crystals:

The IBS co-crystals were prepared using different co-formers. The solvent evaporation method was attempted to prepare the co-crystals. IBS and the co-formers’ Benzoic acid, Maleic acid and Succinic acid were weighed as per the molar ratios (1:1 and 1:3). IBS was dissolved in HPLC grade methanol, and the co-former was added and mixed well in a beaker, covered with aluminum foil and kept in the vacuum oven at 37º for 72 h, after which the dried crystals were stored in desiccator⁹.

 

Saturation Solubility Study:

Saturation solubility study of IBS and its co-crystals was performed in 0.1 N HCl and Phosphate buffer pH 6.8.  Studies were performed by taking excess amount of drug in different buffers (duplicate, n=3) and were kept for shaking in water bath shaker (Remi Equipment Ltd., Bangalore) for 24 h at 37^◦C. The saturated solutions were filtered using 0.22 µm membrane filters and were estimated by UV Spectrophotometer at 250.8 nm.

 

Intrinsic Dissolution Study:

In vitro release studies of IBS and co-crystal was carried using USP-II dissolution apparatus (paddle apparatus) at 50 rpm containing an equivalent amount of the formulation to 50 mg of the drug.  The co-crystals were compressed into the disc at 35 kg/cm² pressure. The test was carried out in 900 ml 0.1 N HCl. The dissolution medium was kept in thermostatically controlled water maintained at 37±0.5ºC. 5 ml of the sample was withdrawn at predetermined time intervals, i.e., 10, 20, 40, 60, 80, 100 and 120 minutes and replaced with equal volume of fresh medium in order to maintain sink condition, during every time of sample withdrawal. The samples were analyzed using UV spectrophotometric method at 250.8 nm. The experiment was performed in triplicate, and percentage drug release was calculated.

 

 

 

 

Solid State Characterization:

Fourier Transform Infrared Spectroscopy (FTIR):

FTIR was performed using Shimadzu FTIR 8300 Spectrophotometer. The samples were mixed with dry potassium bromide, and this mixture was taken in a diffuse reflectance sampler, and IR spectra were recorded and compared in the wavelength region of 400 to 4000 cm^-1.

 

Differential Scanning Calorimetry (DSC):

DSC studies are carried out using a DSC 60 Calorimeter. The samples were hermetically sealed in a flat-bottomed aluminum pans and heated over a temperature range of 0º C - 250º C at the rate of 10º C/min using aluminum as a reference standard.

 

X-Ray Diffraction (XRD)Study:

X-Ray Diffraction (XRD) patterns of the drug and co-crystals were collected  using X-ray diffractometer (X’Pert Powder PAN analytical system, Netherlands) with Cu Ka radiation generated at 40 Ma and 35 kV. The samples were scanned in the range of 5º to 50º for  2 h.

 

RESULTS AND DISCUSSION:

An attempt was made to enhance the solubility of the drug IBS through co-crystallization technology using Benzoic Acid, Succinic Acid, and Maleic Acid as co-formers.IBS is a zwitter ion with pKa’s in the range of 3.3 - 3.9 and 4.2- 4.8 resulting in negligible water solubility in the pH range 3 to 5¹⁰. The pKa of co-formers is, Succinic Acid 3.55, Maleic Acid pKa (Strongest Acidic)3.05 and Benzoic Acid 4.2. IBS co-crystals were formed with Benzoic Acid, and Succinic Acid with stable physical propertywhereas with Maleic Acid co-crystals were not formed. The preparation mixture of IBS with Maleic Acid was liquid in nature.

 

Saturation Solubility Study:

The saturation solubility data of IBS and co-crystals is shown in Table 1. The drug has shown maximum solubility in 0.1N HCl medium. Co-crystals prepared with benzoic acid showed maximum solubility compared to succinic acid. There were two folds increase in the solubility of benzoic acid co-crystals in HCl with 1:3 ratio.

 

Table 1. Results for the Saturation Solubility Study

Intrinsic Dissolution study:

The in vitro drug release profile of optimized co-crystals (1:3 ratio) is shown in Fig 2. The Benzoic Acid co-crystals showed an improved solubility profile that is almost 8 times greater than the original pure drug. Succinic Acid co-crystals showed an improved solubility profile that was 4 times greater than the original pure drug. This indicates the enhanced solubility profile of IBS in the form of co-crystals. Dissolution studies also indicated better performance of Benzoic Acid co-crystals.

 

 

Fig. 2. In vitro drug release profile of co-crystals in 0.1 N HCl

 

Solid State Characterization:

Fourier Transform Infrared Spectroscopy (FTIR)

The infrared spectrum of the pure drug and co-crystals were compared (Table 2). All the characteristic peaks found in the pure drug, IBS were found to be retained in the Benzoic Acid co-crystals and Succinic Acid Co-crystals, indicating that there are no incompatibilities between the co-formers and co-crystals(Fig. 3, 4 and 5) and indicated no change in chemical properties of the drug.

 

 

Fig 3. FTIR spectra of Pure Drug IBS

 

Fig 4. FTIR spectra of Benzoic Acid co-crystal

 

 

 

Fig 5. FTIR spectra of Succinic Acid co-crystals

Table 2. FTIR Peaks of IBS and co-crystals

 

 

Differential Scanning Calorimetry (DSC):

Differential Scanning Calorimetry helps in determination of chemical interactions between the co-crystal and the co-formers. IBS showed a characteristic peak at 190.48°C. Succinic acid and Benzoic Acid Co-crystals showed a characteristic change in peaks with a hollow pattern with decreased intensity of peak. This change in thermograms of the co-crystals could be due to partial amorphization of the drug in co-crystal form (Fig. 6 and 7).

 

 

 

Fig. 6 DSC thermogram of IBS

 

(a)

 

 

(b)

Fig. 7 DSC of a) Benzoic Acid 1:3 Co-crystals and b) Succinic Acid 1:3 Co-crystals

X-Ray Diffraction Study (XRD):

XRD diffractograms of pure drug IBS, succinic acid and co-crystals is shown in Fig. 8 and 9. IBS showed intense diffraction pattern, whereas the diffraction pattern of co-crystals also contained many peaks compared to the drug, with less intensity. However, the intensity of 2-Theta values was drastically reduced in confirming the molecular dispersion of the drug within the co-former.

 

 

Fig. 8 XRD diffractogram of IBS

 

(a)

 

(b)

Fig. 9 XRD diffractograms of a) Benzoic Acid 1:3 Co-crystals and b) Succinic Acid 1:3 Co-crystals

 

CONCLUSION:

An attempt was made to enhance the solubility of the IBS through co-crystallization technology using Benzoic Acid, Succinic Acid and Maleic Acid as co-formers. IBS co-crystals were formed with Benzoic Acid and Succinic Acid as co-formers in the ration 1:3 was chosen for further studies. Intrinsic dissolution of the co-crystals was seen to be enhanced by 4-8 times as compared to the pure drug by in-vitro dissolution studies. There was no significant chemical interaction between the co-formers chosen and IBS. Thus the solubility was increased without any detrimental effect on the active ingredient. Thus, the co-crystallization method appears to be a promising method of choice in case of IBS to get the desired solubility and bio-availability.

 

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6.         Boghra RJ et al. Solubility, dissolution rate and bioavailability enhancement of irbesartan by solid dispersion technique. Chemical and Pharmaceutical Bulletin (Tokyo). 2011;59(4):438-441.

7.         Muankaew  C et al. Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: Influence of pH and excipients. International  Journal of  Pharmaceutics. 2014;474(1-2):80-90.

8.         Regulatory Classification of Pharmaceutical Co-Crystals. Available from URL: https://www.fda.gov/downloads/Drugs/Guidances/UCM281764.pdf.

9.        Thomas J et al. Design and Characterization of Valsartan Co-Crystals to Improve its Aqueous Solubility and Dissolution Behavior. Research Journal of Pharmacy and Technology.2017; 10(1): 26-30.

10.      https://www.fda.gov/downloads/Drugs/Development ApprovalProcess/DevelopmentResources/UCM401182.pdf

 

 

 

 

Accepted on 16.07.2018          © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(9): 3932-3936.