Experimental data of co-crystals of Etravirine and L-tartaric acid

Etravirine is a drug used alongside other medication in the treatment of HIV and is a non-nucleoside reverse transcriptase inhibitor. It is a BCS class IV drug, having low solubility and high permeability (Drugbank, https://www.drugbank.ca/drugs/DB06414) [1]. As a result, large doses of the drug are required for treatment. Two pills have to be taken twice a day, making it a “pill burden” (Intelence, http://www.intelence.com/hcp/dosing/administration-options) [2]. Therefore, attempts of co-crystallizing Etravirine are attractive as the solubility of the drug tends to increase in this solid form (Schultheiss and Newman, 2009) [3]. In this study Etravirine co-crystals were synthesized in the molar ratios 1:1, 1:2 and 2:1 with L-tartaric acid as the co-former. Both slow evaporation and physical mixture was performed to mix the components. DSC values of final products are presented as well as FTIR spectra to observe the altered intermolecular interactions. A chemical stability test was performed after seven days using area under curve data from an HPLC instrument.


a b s t r a c t
Etravirine is a drug used alongside other medication in the treatment of HIV and is a non-nucleoside reverse transcriptase inhibitor. It is a BCS class IV drug, having low solubility and high permeability (Drugbank, https://www.drugbank.ca/drugs/ DB06414) [1]. As a result, large doses of the drug are required for treatment. Two pills have to be taken twice a day, making it a "pill burden" (Intelence, http://www.intelence.com/hcp/dosing/admin istration-options) [2]. Therefore, attempts of co-crystallizing Etravirine are attractive as the solubility of the drug tends to increase in this solid form (Schultheiss and Newman, 2009) [3].
In this study Etravirine co-crystals were synthesized in the molar ratios 1:1, 1:2 and 2:1 with L-tartaric acid as the co-former. Both slow evaporation and physical mixture was performed to mix the components. DSC values of final products are presented as well as FTIR spectra to observe the altered intermolecular interactions. A chemical stability test was performed after seven days using area under curve data from an HPLC instrument.

Data format
Analyzed, processed Experimental factors -Prepared co-crystals were stored in ambient conditions prior to analysis -Saturated solution was diluted by a factor of ten for solubility analysis within appropriate range Experimental features Preparation of co-crystals of Etravirine and L-tartaric acid in molar ratios 1:1, 1:2 and 2:1 with slow evaporation method. Solid state characterization of products using DSC and FTIR in addition to chemical stability analysis.

Manipal, Karnataka, India
Data accessibility Data are available in article

Value of the Data
Mixture of L-tartaric acid and Etravirine shows different IR spectra compared to pure drug. Further solubility studies of the co-crystals could investigate possible improved drug performance. Chemical stability proved for molar ratio 1:1 and 1:2 of Etravirine and L-tartaric acid.

Data
Data in this article shows the characteristics of products prepared from different molar ratios of Etravirine and L-tartaric acid. Table 3 shows the melting points of pure reactants and of the product samples and Fig. 1 displays the complementary thermograms. Fig. 2 displays the FITR spectra of the samples. All three sample batches prepared by slow evaporation method show a broadening of the primary amine peak (3300-3500 cm -1 ) whereas the physical mixture does not. Chemical stability data is shown in Fig. 3 and Table 4 where the retention peak for Etravirine is the only area of significant size for both 0 and 7 days.

Materials
Etravirine was received from Apotex Research PVT LTD, Bangalore. L-tartaric acid was purchased from Sigma-Aldrich, Mumbai. HPLC grade acetonitrile was obtained and analytical grade methanol was obtained from FINAR Limited, Ahmedabad and acetone from Merck Life Sciences Private Limited, Mumbai. A Milli-Q purification system (Siemens AG, Germany) was used in the laboratory to obtain HPLC grade water.
L-tartaric acid was selected as co-former after promising results in increased solubility with DLtartaric acid as co-former from a research study performed at Manipal College of Pharmaceutical Sciences during the fall of 2016 [4]. Etravirine has 2 hydrogen bond donor sites and 7 hydrogen bond acceptor sites resulting in a high probability of co-crystal formation with co-formers.

Co-crystal preparation
Co-crystals were prepared in molar ratios 1:1, 1:2 and 2:1 of Etravirine and L-tartaric acid respectively through slow evaporation method. Desired amount of co-crystal component was weighed and saturated solutions of the components were prepared separately by adding approximately 1 mL solvent. The solvent used was acetone: methanol (50:50% v/v). The saturated solutions were mixed in a common vial and vortexed for 10 minutes. After, the solution was spread evenly on a petri dish and covered with aluminum foil with holes. The solution evaporated at room temperature until the sample was completely dry. The petri dish was scraped and the co-crystals were collected and stored for further analysis. 500 mg of co-crystals were produced in triplicate batches (n¼ 3) for each molar ratio as described in Table 1.
A single physical mixture sample of molar ratio 1:1 was also prepared in a plastic vial by mixing with a micro spatula for two minutes and then shaking the vial manually for five minutes.

FTIR
A Shimadzu FTIR-8300 was used to acquire the FTIR spectra of the co-crystals. One FTIR sample per batch was prepared in addition to the physical mixture making 10 samples in total. The samples were dispersed in KBr which was then grinded to a disk by applying pressure. The measured range was 4000-500 cm −1 with 25 scans.

HPLC
The co-crystal purity was analyzed with a Shimadzu LC-10 series chromatographic system. The system contained a controller unit (SCL-10A VP), a degasser unit (DGU-20A5), a quaternary gradient pump (LC-20AD), a refrigerated auto sampler (SIL-20AC HT) and a PDA detector (SPD-20A). The buffer solution was filtered using a vacuum-filtration apparatus (Alltech Associates) with a 0.45 μm filter (Pall Life Sciences). The mobile phase was degassed by sonication in Equitron ultrasonic bath. For the stationary phase a Hypersil BDS C 18 (150×4.6 mm×5 μm) column was used and the mobile phase was a mixture of acetonitrile: phosphate buffer (60:40% v/v). The flow rate was 1 mL/min and detection wavelength at 304 nm at 30°C.

HPLC sample preparation
The equivalent of 10 mg Etravirine in each co-crystal form was weighed out from a mixture of product batches with the same molar ratios. A stock solution was created by adding amount from Table 2 in 10 mL acetonitrile: methanol (50:50% v/v). 0.5 mL was pipetted from stock and diluted to   10 mL with the same solvent. 0.3 mL of diluted solution was further diluted with 1.2 mL acetonitrile: phosphate buffer (60:40% v/v). The product analysis was performed in triplicate (n ¼3) for each molar ratio.

Stability studies
After 7 days, an additional HPLC test was run as described above on the co-crystals to examine their chemical stability and the possible appearance of degradation products. Samples were prepared in duplicates (n ¼2) for each molar ratio.