Preparation and Characterization of Flurbiprofen Co-crystals By Using Factorial Design

 

Zalte A. G.*, Saudagar R. B.

R. G. Sapkal College of Pharmacy, Anjaneri, Nashik.

*CorrespondingAuthorE-mail:zalteamar@gmail.com

Flurbiprofen is a non-steroidal anti-inflammatory BCS class II drug of low solubility and high permeability. Pharmaceutical co-crystals of  Flurbiprofen were prepared with co-crystal former as benzoic acid  to improve drug its physicochemical parameters. Solvent drop grinding method was found to be successful to prepare Flurbiprofen co-crystals. All new crystalline forms were characterized by IR  spectroscopy, differential scanning calorimetry, and X-ray diffraction  to confirm their purity and homogeneity. Co-crystals with benzoic acid showed a faster powder dissolution rate as compared with pure active pharmaceutical ingredient (API). Co-crystals of Flurbiprofen with benzoic acid showed increase in solubility by 6.68 fold as compared with pure active pharmaceutical ingredient (API). The study showed that co-crystals is an emerging alternative to modify and enhance physicochemical properties of drug to enhance their pharmaceutical properties.

 

 

 

1. INTRODUCTION:

The improvement of the biopharmaceutical activity of active pharmaceutical ingredients (APIs) has become a major concern in the pharmaceutical industry. Branded and generic pharmaceutical industry use their efforts and resources on the discovery of new crystalline forms of an APIs. This intense research has been driven by the need for improving undesirable properties of APIs witnessed in the commercialization pipelines^1,2. Pharmaceutical co-crystals is emerging trend to improve physicochemical and mechanical properties such as solubility, dissolution rate, stability hygroscopisity, compressibility and in vivo performance without altering their pharmacological behavior and, hence, are a potential new alternative in the selection of optimal solid forms in drug product development^3,4.

 

Pharmaceutical co-crystals can be defined as crystalline complexes of two or more neutral molecular constituents bound together in the crystal lattice through non-covalent interactions, primarily hydrogen bonding⁵. The resulting multi-component crystalline phase maintains the intrinsic activity of the parent API. The screening of co-crystal is based upon some traditional methods such as solvent evaporation, crystallization from melts and  grinding^6,7. Co-crystals can be considered for non-ionizable drugs for which salts cannot be attained. Also, for ionizable drugs, the number of suitable co-crystal ligands can exceed the number ofsuitablecounterions⁸.

 

Flurbiprofen (Figure 1) is a non-steroidal anti-inflammatory agent, one of the propionic acid group, which has significant anti-inflammatory, analgesic and antipyretic properties. Clinically, it is used for the treatment of rheumamatoid arthritis, degenerative joint disease, osteoarthritis, ankylosing spondylitis, acute musculoskeletal disorders, low back pain and allied conditions. It is designed as chemically as  2-(3-fluoro-4-phenylphenyl) propanoic acid. It acts as  the anti-inflammatory effect of flurbiprofen occurs via reversible inhibition of cyclooxygenase (COX), the enzyme responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2) in the prostaglandin synthesis pathway. Flurbiprofen is BCS class II drug which means it is having low solubility.

 

Figure 1: Structure of Flurbiprofen

 

Pharmaceutical co-crystals of Flurbiprofen were prepared with cocrystal formers as benzoic acid to improve drug solubility. Solvent drop grinding method was used as it is a ecofriendly method. New crystalline forms were characterized by IR spectroscopy, differential scanning calorimetry, and X-ray diffraction to confirm their purity and homogeneity.

 

2. MATERIALS AND METHODS:

2.1 Material:

Flurbiprofen was received as a gift sample from the Agio Pharmaceutical Ltd. Pune, Maharashtra, India. Other chemicals and solvents were obtained from different commercial suppliers.

 

2.2 Preparation of Co-crystals:

Pharmaceutical co-crystals of Flurbiprofen were prepared with different co-crystal formers using solvent drop grinding method. After performing trail batches with different coformers Flurbiprofen-  Benzoic acid co-crystal was selected depending upon solubility rise. Solvent drop grinding method was selected in which molar ratio of drug and conformer taken  in a pestle and mortar for optimized minutes with addition of a few drops of methanol.  . The solid powder was then scratched from walls of mortar and stored in vial. The ratio and grinding time were optimized by using full factorial design. The solid obtained in experiments were then characterized using various analytical techniques.

 

2.3 Experimental design for preparation of co-crystals of Flurbiprofen using solvent drop grinding method:

Three factors at two levels were chosen to set up a 3² factorial design. Table 1 gives the factors and levels used while Table 2  gives details of the nine experiments planned.

 

Table 1: Factors and their levels

 

Table 2: Details of the nine formulations in the 3² factorial design

 

3. PRELIMINARY CHARACTERIZATION:

3.1 Melting point

Melting point of the sample Flurbiprofen- benzoic acid co-crystals were determined by open capillary method by using melting point apparatus.  The melting point was done in triplicate. (Omega Scientific Industries, India).

 

3.2 IR Spectroscopy

Infrared spectroscopy analysis Flurbiprofen- benzoic acid co-crystals was performed by Attenuated Total Reflectance (ATR Bruker Alpha).

 

3.3 Differential scanning calorimetry

The DSC thermogram of  Flurbiprofen- benzoic acid co-crystals was recorded by differential scanning calorimeter equipped with a computerized data station. The DSC measurements were performed on a DSC 60, Shimadzu, Japan instrument. Accurately weighed sample were placed in a sealed aluminium pans before heating under nitrogen flow (20ml/min) at a scanning rate of 10⁰c/min. An empty aluminium pan was used as a reference. Melting point was determined for identification of API and cocrystal former.

 

3.4 X-ray Diffraction

For characterization of crystalline state, the powder x-ray diffraction (XRD) pattern of  Flurbiprofen- benzoic acid co-crystals was determined. Powder X-ray diffraction (XRD) was carried out using a Bruker AXS Advance D-8  scanner with filter Ni, Cu-  Kά  radiation, voltage 40kV and a current 20mA. The scanning rate employed was 1⁰/min over the 5⁰ to 50⁰ diffraction angle (2Ɵ) range.

 

3.5 Scanning Electron Microscopy

Scanning electron microscopy of  Flurbiprofen- benzoic acid co-crystals was carried to determine the external morphology. The sample was mounted directly onto the SEM sample holder using double sided sticking tape and

images were recorded at the required magnification at acceleration voltage of 10 kV using scanning electron microscope (JSM 6930, Jeol Datum Ltd. Japan).

 

3.6 Phase Solubility

The phase solubility of Flurbiprofen- benzoic acid co-crystals was determined. The solubility of drug and cocrystals were determined by taking an excess amount of drug (50 mg), cocrystals (equivalent to 50 mg of drug) and added them in 10 ml of above solvent, in vials. The samples were kept at equilibrium for a period of 72 hrsin incubator at 37± 0.5⁰C with occasional shaking. The supernatant collected from vials was filtered through Whatman filter paper and analyzed by UV-Visible spectrophotometer (V630, Jasco) at respective wavelength.

 

3.7 Flow properties

Flow properties and compressibility were determined by determining bulk density, tapped density angle of repose, compressibility index and Hausner ratio.

 

4. RESULT AND DISCUSSION:

4.1 Melting point determination:

Melting point of the drug sample and cocrystals were determined by open capillary method by using melting point apparatus and found to be shown in Table 3.

 

Table no. 3: Melting point of Flurbiprofen, Co-crystal former and co-crystals

4.2 IR Spectroscopy:

 

Figure 2: IR spectra of Flurbiprofen, Flurbiprofen- Benzoic acid co-crystals co-crystals, benzoic acid

 

Infrared spectroscopy helps in preliminary identification of new crystalline form. From comparison indicated shifts of peak represents the new crystalline form. It is confirmed from shift at –C=O stretch and also C-O stretch strongly indicate formation of hydrogen bond in between Flurbiprofen and Benzoic acid.

 

4.3 Differential Scanning Calorimetry (DSC):

 

Figure 3:  A: DSC thermogram of Flurbiprofen.              

 

 

B: DSC thermogram of Flurbiprofen- benzoic acid Co-crystals.

 

 

The thermogram of Flurbiprofen were recorded by using a differential scanning calorimeter equipped with a computerized data station. The thermogram of Flurbiprofen had shown a single endothermic peak maxima at 116.34⁰C due to melting of drug. Flurbiprofen- Benzoic Acid Co-Crystals co-crystals had shown a single endothermic peak maxima at 66.68⁰C due to melting of cocrystals. The thermal behaviour was distinct, with a different melting transition from that seen with either of the individual component; this suggest formation of new phase cocrystals. The melting point of cocrystals was found to be below the melting point of both the drug and cocrystal former. A single endothermic transition for the cocrystals indicates the absence of any unbound or absorbed solvent or water and also demonstrates the stability  of the phase until the melting point.

 

4.4 X-Ray Diffraction:

 

Figure 4: A: XRD Patterns of Flurbiprofen.                                                                                                                                                                             

 

B:XRD Patterns of Flurbiprofen- benzoic acid Co-crystals.

 

Flurbiprofen and Flurbiprofen- Benzoic Acid Co-Crystals exhibited intense crystalline peak between 5⁰ to 50⁰. Characteristic diffraction peaks at 9.7⁰, 12.75⁰, 16.65⁰, 19.99⁰, 23.21⁰ and 28.91⁰were observed with intense peak at 20.2⁰ indicating crystalline nature of Flurbiprofen. While Flurbiprofen- Benzoic Acid Co-Crystals shows characteristic at  and intense peak was observed at 16.7⁰ indicating crystalline nature of Flurbiprofen- Benzoic Acid Co-Crystals. The shift in intense peak indicate formation of new crystalline form. 

 

4.5 Scanning Electron Microscopy:

 

Figure 5: A: Scanning Electron Microscopy  of Flurbiprofen.                                                      

 

B: Scanning Electron Microscopy of  Flurbiprofen- Benzoic acid co-crystals.

 

 

In case of pure Flurbiprofen indicated needle shaped fracture surface, but the SEM of Flurbiprofen- Benzoic Acid Co-Crystals co-crystals indicated change in surface morphology, development of irregular plate shaped crystal were seen from Figure 5.

 

4.6 Phase solubility:

Solubility studies were performed in order to analyze solubility enhancing properties of cocrystals. Solubility studies gave the basis for selection of best ratio that is to be forwarded for formulation. The results of the same are shown in Table no. 4.

Table  no. 4: Phase solubility of  Flubiprofen and Flubiprofen Benzoic acid co-crystals

 

4.7 Flow properties:

The flow properties of Flurbiprofen, Flurbiprofen Benzoic acid co-crystals have been determined and compared in Table no. 5 shows the flowability represented in terms of the angle of repose, Carr’s index and Hausner ratio of cocrystals were much improved compared to those of the original drug crystals.

 

Table  no. 5: Comparison of flow properties of   Flurbiprofen and Flubiprofen Benzoic acid co-crystals

 

4. 8 Formulation of Flurbiprofen- Benzoic Acid Co-Crystals tablets:

The optimized formulae for Flubiprofen Benzoic acid co-crystals tablet had decided on trial and error basis of hardness and disintegration time of tablets.

 

Table  no. 6: Formulation of Flurbiprofen- Benzoic Acid Co-Crystals tablets

 

 

4.9  In-vitro drug release study of Flurbiprofen- Benzoic Acid Co-Crystals tablets vs Marketed Formulation:

The drug release study of tablets formulation was carried out to compare the dissolution efficiency of Flubiprofen Benzoic acid co-crystals tablets marketed tablets.

 

Figure 5: Comparison of % Drug release in phosphate buffer pH 6.8

 

Marketed tablet (Arflur) gave 82.52% drug release in phosphate buffer pH 6.8 after 1 hour. While co-crystals tablet gave 96.02% release in phosphate buffer pH 6.8 after 1 hour, This show that cocrystal formulation shows better result than marketed tablet.

 

5. CONCLUSION:

Flurbiprofen cocrystals was formed with Benzoic acid cocrystal former to enhance physicochemical problems associated with an API. Cocrystals of Flurbiprofen with benzoic acid was prepared by using solvent drop grinding method. Cocrystals was confirmed by melting point, ATR-IR, DSC, XRD, SEM.  Cocrystals of Flurbiprofen with benzoic acid showed increase in solubility (6.68 folds as compared with API) and dissolution profile.  The study successfully demonstrate that co-crystals has shown increased solubility, dissolution, flow properties and compressibility.

 

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Received on 05.01.2018         Modified on 20.02.2018

Accepted on 28.02.2018         © AJRC All right reserved