Design and Characterization of Valsartan Co-Crystals to Improve its Aqueous Solubility and Dissolution Behavior

 

Jino Elsa Thomas, Usha Y Nayak*, Jagadish PC, Koteshwara KB

Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal – 576104

*Corresponding Author E-mail: ushaynayak@gmail.com

 

ABSTRACT:

The aim of the work was to prepare co-crystals of valsartan, 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 was found to be suitable co-former to prepare co-crystals with good physico-chemical properties. The solid state characterization of co-crystals were studied by FTIR, DSC and XRD. The co-crystals were evaluated for the saturation solubility and dissolution studies. Solubility study in distilled water indicated low solubility of valsartan (198.5 µg/ml), there was 2.6 fold increase in the solubility of co-crystals prepared using succinic acid, with 1:5 drug to co-former ratio (520.6 µg/ml). 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 suitable alternative to increase the solubility and dissolution rate of valsartan.

 

KEYWORDS: Valsartan, co-crystals, solvent evaporation, co-formers, succinic acid, bioavailability

 

 

 

 

 


INTRODUCTION:

Active Pharmaceutical Ingredients (API) can be present in a number of forms such as salts, polymorphs, hydrates, solvates, co-crystals and amorphous solid. Co-crystals are crystalline substances consists of two or more components that form a distinctive crystalline structure exhibiting unique physicochemical properties compared with pure crystal forms of APIs. These physical properties include improved solubility and physical stability. The dissolution rate and solubility of different crystal forms has strong influence on bioavailability1. In co-crystals, the molecules interact by non-ionic interactions and the components are in neutral state without altering the intrinsic activity of the drug molecule.

 

It is important that a co-crystal is neither heterogeneous phase nor a mixture of single component crystalline phases. Non-ionic intermolecular interactions and geometries are responsible for the generation of supramolecular networks that may leads to crystalline phases.  Co-crystals are formed by hydrogen bonding or vander Waals interactions between the drug and the co-former2, 3. As per the FDA, co-crystals are considered as dissociable molecular complexes. Advantages of co-crystals over other solid forms are that the drug from weakly ionizable to non-ionizable can form co-crystals and the co-crystal former can be a food additive, excipient, any inactive component and even other drugs too4. Valsartan is an Angiotensin- II receptor antagonist (ARB), belongs to BCS Class II with low solubility and high permeability, used in hypertension. Its clinical application is limited by the poor solubility and low bioavailability (23%). As it is practically insoluble in water so it shows variability in GI absorption. Attempts were made to improve the solubility of valsartan by complexing it with Hydroxypropyl-\boldbeta-Cyclodextrin5.  Dixit et al prepared self-emulsifying drug delivery system of valsartan to enhance diffusion rate and bioavailability6. Poloxamer-based solid dispersions and physical mixtures containing valsartan was attempted by Ha et al.7. Yan et al., prepared valsartan-loaded solid dispersion for enhanced bioavailability without any crystalline changes8. Chella et al. employed liquisolid compact technique for improvement of the dissolution rate of valsartan9. In our earlier attempt self-nanoemulsifying drug delivery system of valsartan was prepared for oral bioavailability enhancement10.  Recently co-crystals are popularized for the ease of commercialization, the present work attempted to formulate the co-crystals of valsartan using different co-formers. The presence of functional groups such as carboxylic acids, amides and alcohols in the drug to form supramolecular heterosynthons are the prerequisite for the formation of co-crystals. Valsartan has two carbonyl groups, carboxyl carbonyl and amide carbonyl (Fig. 1). Presence of carboxyl acid in valsartan, can easily forms co-crystal with other suitable components. The valsartan co-crystals were attempted using co-formers containing carboxylic acid group such as glutaric acid, maleic acid and succinic acid (Fig. 1) by solvent evaporation method and vacuum oven method. The co-crystals were evaluated for drug content, solubility, dissolution and solid state characterization.

 

Fig. 1 Structure of valsartan and different co-formers

 

MATERIALS AND METHODS:

Materials:

Valsartan was obtained as gift sample from Lupin Research Park, Pune, India. Maleic acid (molecular weight 116.07) was procured from HiMedia Laboratory Pvt. Ltd., Mumbai, India. Nicotinic acid (molecular weight 123.11) and succinic acid (molecular weight 118.09) were procured from SRL Pvt. Ltd., Mumbai, India. All other chemicals were of analytical grade.

Preparation of co-crystals:

The valsartan co-crystals were prepared using different co-formers such as glutaric acid, maleic acid and succinic acid. The solvent evaporation and vacuum oven methods were attempted to prepare the co-crystals.

 

Solvent Evaporation Method:

The required amount of drug and co-crystal former was weighed at different molar ratios (drug: co-former 1:1 (S1), 1:2 (S2), 1:3 (S3), 1:4 (S4) and 1:5 (S5)) and dissolved in 3 ml methanol separately. Then both the solutions were mixed together and the solvent was evaporated in the water bath at 60ºC for about 30 min. After complete evaporation of the solvent the co-crystals formed were dried in a vacuum desiccator for 24 h.

 

Vacuum Oven Method:

Methanolic solutions of drug and co-formers at different molar ratios similar to above (S1V to S5V) were placed in vacuum oven at 400mmHg at 40 ºC for 24 h. The crystals formed were stored in a vacuum desiccator.

 

Saturation Solubility Study:

For solubility study excess amount of pure drug and co-crystals were added to distilled water to obtain a super saturated solution. The solution was allowed for complete saturation in a water bath shaker at 37ºC for 48 h until equilibrium was achieved. The solution was filtered through 0.45 μm filter (Millipore), the filtrate was diluted and absorbance was measured at wavelength 250 nm using UV-Spectrophotometer (Shimadzu, Japan).

 

Drug content determination of co-crystals:

20 mg of co-crystals were dissolved in 10 ml methanol and vortexed for 5 min. The solution was filtered and after sufficient dilution with phosphate buffer (pH 6.8) analyzed at 250 nm using UV-Spectrophotometer.

 

Dissolution Studies:

The dissolution study of co-crystals was carried out in USP type I dissolution apparatus in two different media. The study was carried out in 900 ml of 0.1 N HCl and phosphate buffer (pH 6.8) separately. Dissolution medium was kept in water bath maintained at 37± 0.5ºC. The co-crystals containing 40 mg of valsartan were filled in capsules (size 1) and placed in the basket. The dissolution was carried out at 100 rpm. At predetermined time intervals of 10, 20, 30, 40, 50 and 60 min, 5 ml of sample was withdrawn and replaced with 5 ml of buffer. Samples were analyzed using UV spectrophotometer at 250 nm.

 

Fourier Transform Infrared Spectroscopy:

The IR spectra of co-crystals were recorded by Fourier transform infrared spectroscopy (FTIR) 8300 Spectrophotometer (Shimadzu, Japan) by potassium bromide pellet technique. Briefly the drug and co-crystals were separately mixed with potassium bromide and compressed into a pellet and then pellet was taken in a diffuse reflectance sampler for recording the spectrum.

 

Differential Scanning Calorimetry (DSC):

Differential Scanning Calorimetry (DSC) studies of drug and the co-crystals was performed using DSC-60 calorimeter (Shimadzu, Japan). The samples were placed in an aluminium pan and press-sealed with a perforated aluminium cover. The samples were heated under nitrogen flow at a heating rate of 5ºC to 250ºC.

 

X-Ray Diffraction 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:

Co-crystals of valsartan were prepared using different co-crystals wherein succinic acid co-crystals were powdery in nature, maleic acid co-crystals were hygroscopic in nature and dry clumps were formed with nicotinic acid. As the amount of co-formers was increased the co-crystals were becoming more hygroscopic. Accordingly 1:3 drug to succinic acid co-crystal formulation was optimized as it was dry and powdery in nature, further increased concentration of co-former formed hygroscopic crystals. For stable co-crystal formation it is essential that the difference between the pKa of drug and co-crystals is to be less than 1. In the present study valsartan, a tetrazole derivative that contains acid (pKa=4.73) and carboxylic (pKa=3.9) groups was used. The pKa of co-formers, succinic acid is 3.55, Maleic acid pKa (Strongest Acidic) 3.05 and nicotinic acid 4.75. Co-crystals using nicotinic acid and succinic acid produced crystals with stable physical property. Method of preparation also had an influence on the formulation of co-crystals. Slow solvent evaporation by vacuum formed crystals with higher crystallinity 11. Succinic acid co-crystals were optimized and further studies were continued with this co-former.

 

Saturation Solubility Study:

The results of saturation solubility are shown in Table 1. Solubility study in distilled water indicated low solubility of valsartan (198.5 µg/ml). There was a remarkable increase in the solubility of co-crystals prepared by solvent evaporation method compared to vacuum oven method. This may be due to the presence of highly water soluble co-formers. Among all the formulations 1:5 ratio of co-crystals prepared by solvent evaporation method showed maximum solubility of about 520.6 µg/ml.

 

Table 1. Solubility study data

Formulation

Solubility (mg/mL)

Formulation

Solubility (mg/mL)

Pure drug

198.5 ± 15.2

 

 

S1

216.8 ± 18.3

S1V

210.8 ± 12.6

S2

295.6 ± 14.2

S2V

230.4 ± 12.2

S3

260.79 ± 18.5

S3V

244.8 ± 14.7

S4

342.1 ± 23.1

S4V

282.8 ± 15.2

S5

520.6 ±  28.8

S5V

365.2 ±  21.4

 

Drug content of co-crystal:

The percentage yield of the co-crystals was more than 98%. The drug content of the formulations was found to be ranging from 80 to 92%.

 

Dissolution Studies:

In vitro release study of the pure valsartan and co-crystals was carried out in USP Dissolution Apparatus – I. The dissolution profile is shown in Fig. 2 and Fig. 3. The rate of dissolution was increased in co-crystals compared to pure drug. In 0.1 N HCl, only 1.3 % drug was released with maximum 20.5 % in 60 min, whereas with S3 formulation 2.4 fold increase in dissolution was observed. The dissolution rate of pure drug in PB pH 6.8 was comparatively higher than 0.1 N HCl owing to the high solubility of the drug in alkaline pH12. 38.2 % release was observed in initial 10 min, accordingly higher release was observed with the co-crystals. Between the two methods of preparation, crystals prepared by vacuum oven method showed low dissolution velocity, which could be due to higher crystalline nature of co-crystals as supported by saturation solubility study.

 

Fig. 2 Dissolution profile of valsartan and co-crystals in 0.1 N HCl


 

Fig. 3 Dissolution profile of valsartan and co-crystals in phosphate buffer pH 6.8

 

Fig. 4 FTIR spectrum of valsartan (VAL) and co-crystals (S3 and S3V)

 

Co-crystals are formed by weak hydrogen bonding with the drug, so these get dissociate easily in biological fluid. As the co-former dissociates, being more water soluble it drawn out of the crystal lattice. The drug becomes more supersaturated, increases the dissolution velocity and thereby the absorption [3].

 

Fourier transform infrared spectroscopy (FTIR):

FTIR study indicates presence of characteristic two carbonyl absorption bands of valsartan at 1730 and 1603 cm−1 carboxyl carbonyl and amide carbonyl stretching vibration, respectively. Whereas in both the co-crystals, these two absorption bands of the drug were observed to be merged and broadened, which could be due to the formation of supramolecular heterosynthons in the co-crystals. Broadened absorption bonds from 2700 to 3900 cm−1 are may be due to the presence of –OH groups of water molecules as the crystals were very much moisture sensitive and the formation of hydrate co-crystals12. The –OH stretching of carboxyl group at 3000 cm−1 was broadened in co-crystals. The shifts in peaks indicates the formation of hydrogen bonding between the drug and the co-formers. Also in the co-crystals energy required for stretching was more compared to pure drug indicating the formation of co-crystals.

 

Differential Scanning Calorimetry (DSC):

In DSC study, valsartan showed melting point at 100ºC with small endothermic peak whereas the thermogram was disappeared in co-crystals indicating dispersion of the drug in the co-crystals. Increase in the solubility of co-crystals may be supported by the complete disappearance of endothermic peak of valsartan in DSC thermograms of co-crystals. Melting point of succinic acid is 184ºC. The appearance of new peaks at 183.29, 191.77 and 193.39 ºC are due to the co-former succinic acid.

 

Fig. 5 DSC thermograms of valsartan (VAL) and co-crystals (S3 and S3V)

 

X-Ray Diffraction Study (XRD):

XRD diffraction of pure drug valsartan, succinic acid and co-crystals was studied as shown in Fig 6.. Valsartan showed broad diffraction pattern with 2-Theta at 14.4º and 21.68º and succinic acid at 15.75º, 19.91º, 26.0º, 32.28º, 38.2º, 50.5º and 58.9º. The presence of several peaks in succinic acid indicated very good crystalline nature of the co-former. In the co-crystals both S3 and S3V, the diffraction pattern contained many intense peaks compared to drug and majority were attributed to the co-former. The intensity of 2-Theta values at 32.28º, 38.2º, 50.5º and 58.9º were drastically reduced confirming the molecular dispersion of the drug within the co-former. The presence of diffraction peak at 19.9 was due to the combined effect of drug and the co-former. However overall comparison of diffractograms, crystallinity was increased in co-crystal formulation due the presence of crystalline co-former along with the drug.


 

Fig. 6 XRD diffractograms of valsartan (VAL), succinic acid (SA) and co-crystals (S3 and S3V)

 

 


CONCLUSION:

Valsartan co-crystals were prepared using succinic acid as co-former by solvent evaporation technique. Co-crystals showed improved solubility and dissolution rate compared to pure drug. Solid state characterization by DSC, FTIR and XRD confirmed the crystallinity and presence of drug in molecular phase of the co-crystals. However there was no change in the chemical nature of the co-crystals compared to pure drug. Thus the prepared crystalline co-crystals may enhance the oral bioavailability of valsartan to provide improved therapeutic action.

 

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Received on 20.09.2016          Modified on 28.10.2016

Accepted on 30.11.2016        © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(1): 26-30.

DOI: 10.5958/0974-360X.2017.00007.5