1. 13th International Symposium ,CRS Mumbai, 22nd - 23rd January 2013
CO-CRYSTALS OF POORLY SOLUBLE DRUG, DIACEREIN USING NICOTINAMIDE AS CO-FORMER
Banerjee J.1, Joshi A.2, Misra M Department of Pharmaceutics,NIPER Ahmedabad, c/o B.V. Patel PERD Centre, Ahmedabad Department of Pharmaceutics, B. V. Patel PERD Centre, Ahmedabad
Solubility enhancement of active pharmaceutical ingredients is a challenging task. Pharmaceutical co-crystals, also known as high throughput crystallization approach, have gained an interest recently.
Because of their physical and pharmacokinetic properties they can modify and improve the properties of pure crystals and in particular the API that constitutes the co-crystal.
In current work, co-crystals of Diacerein were prepared. Diacerein is a semi-synthetic anthraquinone derivative having interleukin-1 inhibitory property which is used as an anti-arthritic.
By virtue of the fact that diacerein has low solubility(0.01mg/ml) in water, the discovery & Identification of new forms of diacerein is relevant to improve its physical and/or chemical properties.
Nicotinamide is a GRAS category co crystallizing co- former. It is a primary amide with two hydrogen bond donors (NH2) and an acceptor (C=O). It demonstrate a remarkable ability to form hydrogen bonds.
Nicotinamide has also been indicated in reducing inflammation due to arthritis. All these properties makes nicotinamide, an excipient of choice for the current work.
To prepare and characterize co-crystals of diacerein using nicotinamide as co-former
To study the effect of co-crystallization on solubility of diacerein
Preparation of Co- crystals: Three methods were evaluated for the formation of co-crystal of diacerin with nicotinamide as a co-former.
Neat grinding method: Diacerein and nicotinamide in 1:1, 1:0.5, 1:2 molar ratios were grinded manually for 60 minutes.
Solvent drop grinding method: Diacerein and nicotinamide in 1:1, 1:0.5, 1:2 molar ratios were taken and grinded manually in presence of methanol for 60 minutes.
Reaction crystallization method: Nicotinamide in molar ratio was dissolved in solvent to prepare a saturated solution and heated at 70ºC to which small quantities of diacerein was added and completely dissolved. The solutions was cooled and allowed to precipitate followed by complete evaporation of solvent. The prepared co- crystals were dried and stored at room temperature.
B. Characterization of co-crystals
The melting point of drug, co-former and co-crystals were measured on melting point apparatus (Veego VMP 3DS).
Thermal analysis of drug, co former and co-crystals was carried on DSC.
Fourier transform infrared (FTIR) studies for the pure drug, co former and the combined molar ratios, spectra was obtained in range of cm-1 to confirm the formation of co-crystals.
C. Solubility determination of pure drug & co-crystals
Calibration curve for diacerein was prepared in aqueous medium.
The solubility studies were performed for pure drug, co-former & the co-crystals.
A saturated solution of drug, drug-co-former were equilibrated for 72 hour followed by centrifugation at 5000 rpm for 30 minutes.
The supernatant (250 µl) was analyzed by UV visible spectrophotometer for solubility determination.
It was found that only solvent assisted grinding method with methanol as solvent resulted in the formation of co-crystals of diacerein- nicotinamide at API-Co-former molar ratio of (1:1) and (1:0.5).
The DSC curves confirms the co-crystal formation with a endothermic peak at ºC. The appearance of a new peak which is intermediate between the peak of drug and co-former indicates the formation of a new solid phase.
INTRODUCTION
EXPERIMENTAL METHODS
RESULTS & DISCUSSION
OBJECTIVES
Table.1. Observation for melting point determination of drug, nicotinamide & co-crystal
Table. 2. Observed peak shifts due to co-crystallization in FT-IR (drug vs co-crystal)
FT-IR results indicate a difference in superimposed spectra of pure drug, co former and prepared co crystals, the region of 2500 cm-1 to 3500 cm-1. There is no significant shift in lower wave numbers indicating the non- proton transfer negating the chances of salts formation. The FT-IR spectra of the diacerin, nicotinamide and co-crystal are shown below
S. No
Sample
Observed melting point
Reported melting point 1
Nicotinamide
º C
128 º C 2
Diacerein
256 º C
258 º C 3
Dia-Nic-1:1 neat grinding
º C - 4
Dia-Nic-phys.mixture
131 º C, 183 º C 5
Dia-Nic-MeOH grinding
183 º C º C
Fig.1.Comparative DSC thermograph for diacerein, Nicotinamide , physical mixture & Dia-Nic (1:0.5) MeOH grinding
Fig.2. Calibration curve of diacerein in aqueous medium
S.No
Peak assigned in diacerein
Frequency (cm-1 )
Shifts observed (cm-1) 1
C-H, stretch, aromatic 2
C-H stretch, aliphatic 3
C=O, stretch, ketone
A 3-fold increase in solubility was observed in case of Dia-Nicotinamide (MeOH)
grinding as compared to the drug alone.
Table.3. Solubility of drug vs co-crystal
Nicotinamide in a ratio of (1:0.5) was found to co-crystallize with diacerein.
Solvent drop grinding was found to be the best method for preparation.
DSC studies confirmed the formation of a new solid phase.
FT-IR studies confirmed the hydrogen bond formation between drug & co-former.
Solubility of co-crystals was found to be better than the diacerein alone.
S.No
Sample
Ratio
solubility 1
Diacerein -
12 µg/ml 2
Dia-NIC (SAG)
1:1
38.8 µg/ml
Basavoju, S., et.al., Pharm. Res. 2008, 25,
Dabre et al., 2010,US/ .
CONCLUSIONS
ACKNOWLEDGEMENTS
The authors would like to acknowledge Elder Pharmaceuticals for the gift sample of diacerein, the management of National Institute of Pharmaceutical Education and Research & B.V Patel PERD centre, Ahmedabad, for providing the necessary facilities to carry out the research work.
REFERENCES
13th International Symposium ,CRS Mumbai, 22nd - 23rd January 2013