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Differential scanning calorimetry was used as a screening technique for assessing the compatibility of Sitagliptin with some currently employed pharmaceutical excipients. The influence of processing effects (simpleblending, co-grinding or kneading) on drug stability was evaluated. On the basis of DSC results, Sitagliptin wasfound to be compatible with micro crystalline cellulose, cross carmelloseand pregelatinized starch.Some excipient interactionwas observed with magnesium stearate,Ascorbic acid and Citric acid. All the excipients selected were compatible with the API. X-Ray Diffractometry (XRD) and FT-IR are used as supportive tools in interpreting the DSC results.
Keywords: Sitagliptin, Excipients, Compatibility, DSC, XRD, FT-IR.
Pharmaceutical excipients are substances other than the active drug or prodrug that has been appropriately evaluated for safety and is included in a drug delivery system to either aid processing of the system during manufacture, or protect, support or enhance stability, bioavailability or patient acceptability, or assist in product identification, or enhance any other attribute of the overall safety and effectiveness of the drug product during storage or use. Excipient incompatibilities are of three types namely physical, chemical and physiological. They have the ability to implicate drug stability,product manufacture,drug release (dissolution; both in vitro and in vivo),therapeutic activity, andside effect profile.However it must be accentuate that excipient interactions are not always detrimental. Sometimes they can be advantageous. There is no universal accepted protocol for evaluating the drug compatibility with different excipients. Differential scanning calorimetry is widely used for evaluating the drug-excipient interactions.Drug-excipient interaction study at an early stage of product development is an important exercise in the development of a stable dosage form. However, no universally accepted protocol is available for evaluating the compatibility of drug with different excipients. Some of the reported methods have poor predictive values and few of them are labor intensive and time consuming. For example, differential scanning calorimeter (DSC) has been proposed as a rapid method for evaluating the drug-excipient interaction [1-6]. Though it has certain advantages, such as requirement of small sample size and fast results, there are certain limitations also. This is because of exposure of drug-excipient mixture to high temperatures (up to 300 -C or more), which, in real situations, is not experienced by the dosage form. Therefore, the DSC results should be interpreted carefully, as the conclusions based on the DSC results alone can be often misleading and inconclusive. Hence techniques like X-ray Diffractometry, FT-IR, and Microscopy are used as complimentary techniques for drawing accurate conclusions. Sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate. Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate. It is available as JANUVIA tab (Sitagliptin), JANUMET tab (Sitagliptin - Metformin), JUVISYNC tab (sitagliptin and simvastatin) and JUVICOR tab (sitagliptin and simvastatin). The objective of this work is to investigate the effects of different excipients and explain the excipient-API interactions and to undertake the compatibility of Sitagliptin, an oral hypoglycemic agent, with a number of commonly used tablet excipients (diluents, binders, disintegration agents and lubricants).
Sitagliptin phosphate was kindly given as a gift sample by Dr. Reddys Ltd. India and used after recrystallization from ethanol. The following excipients were investigated: Magnesium Stearate, Micro Crystalline Cellulose, Cross Carmellose, Ascorbic acid, Citric acid, and Pregelatinized starch.
2.2. Preparation of samples
Each material was sieved and respective 75-150 micro granulometric fractions were selected. Physical mixtures of sitagliptin and each selected excipient were prepared in the ratio of 1:1 w/w by gently bending in an agate mortar with a spatula. The blends were considered homogenous when DSC traces of three samples from the same preparation were superimposable. Co-ground mixtures are obtained by grinding a portion of each physical mixture with a pestle for 15 min. kneaded mixtures were prepared by slurring a portion of each physical mixture with a minimum amount of ethanol and triturating thoroughly to obtain a paste which was dried under vacuum at room temperature up to a constant weight.
2.3. Differential scanning calorimetry
Samples of individual components as well as each drug - excipient combination were weighed o a Sartorius balance (CD225D,22308105 Germany). The sample was taken directly in pierced Al pans (5- 10 mg) and scanned in the temperature range 40 - 250oc under static air, with a heating range of 10 K min-1, using TA instruments THERMAL ANALYSIS(Q series)equipped with DSC 25 cell.
2.4. X-ray Diffractometry
X-ray powder diffraction patters were obtained using a PANalytical Empyrean (Netherlands) X-Ray Diffractometer, at a scan rate of 20 min-1 over the 3-70o 2Éµ range. Samples are prepared by making 1:1(w/w) blend of API and excipient and fine powders were dispersed on the discs. It was operated and processed using High score software.
FT-IR spectra of drug, excipients and grinding mixtures were recorded on a Perkin-Elmer Model 1600 apparatus using KBr stressed discs in the range of 4000-400 cm−1.
3. Results and discussion
3.1. Thermal behaviour of Sitagliptin
The DSC curve obtained for Sitagliptin is presented in Fig.1. Thermal decomposition of Sitagliptin in a nitrogen atmosphere occurs in one event and starts at 217 -C, as presented in Fig. 1. The DSC curve of Sitagliptin (10oC min−1) presents a sharp endothermic event at 212.1 -C (Tonset= 208.7 -C; Hfus = 119.4 J g−1) indicating the melting.
3.2. Compatibility study with excipients
The DSC curves of Sitagliptin and each of the investigated excipients were compared with those obtained from their 1:1 (w/w) mixtures. The 1:1 (w/w) ratio was selected to maximize the likelihood of observing any interaction. In order to evaluate the effect of mechanical manipulation on the physicochemical stability of the drug, three different techniques were used to prepare drug-excipient samples: simple blending, co-grinding and kneading. When important modifications of the drug thermal profile were observed in DSC traces of mixtures, X-Ray Diffractometry (XRD) and FT-IR were used as complementary techniques to assist in the interpretation of DSC results.Thermal parameters were calculated from DSC curves of individual components and drug-excipient combinations i.e freshly prepared, dry ground and kneaded (i.e. wet ground) mixtures, were presented in Table 1. While Fig. 2a, 2b illustrate selected thermo grams of various systems investigated.The excipients Croscarmellose, Pregelatinized starch and MCC exhibited a shallow broad endothermic effect in the range of 50-100 oC range due to loss of water from the polymer (dehydration).In the presence of acid excipients like citric acid and ascorbic acid, drug stability seemed to be seriously affected, wherethe marked broadening and downshift of thermal effects of individual components, followed by exothermic or endothermic decomposition was observed Fig.2a. It is present even in DSC traces of freshly prepared blends.Acid andbase interactions were probably responsible for some interactions. It can be ascertained from the fact that sitagliptin forms salt with citric acid as reported in the European patentcould be the reason behind this and it can be analogouslyhypothesized with ascorbic acid (pKa 4.2). X-ray diffraction showed, absence of significant interactions at room temperature in mechanically treated samples (Fig.3a,3b). Heating was then the driving force of the decomposition process between Sitagliptin and the partner of acidic character.The thermogram of magnesium stearate showed an endothermic peak at 98.3°C and followed by a small shoulder at a higher temperature, probably due to the presence of the corresponding palmitate salt impurity. The DSC curves of 1:1 (w/w) drug-excipient mixed systems displayed a single endothermic peak at a much lower temperature (around 66-70°C) in comparison with the melting points of the pure components. With respect tocitric acid kneaded mixture was not possible because of hydrolysis reaction between solvent used for kneading i.e ethanol and the acid. Ethanol was selected as a solvent for kneading and recrystallization as Sitagliptin was insoluble in this solvent. In the DSC thermogram of magnesium stearate, an endothermic peak was observedat 98.3°C with an irregular thermogram. The DSC thermogram of the SIT-magnesium stearate mixture showed disappearance of the Sitagliptin peak (Fig. 1e), which suggested that there might have been some physical incompatibility between Sitagliptin and magnesium stearate. But when XRD of the same were observed it showed, Sitagliptin showed the characteristic diffraction pattern at 4.5, 9.2, 12.2, 14, 15.1, 18.2, 20.5, 23.9, 24.5, 25.6 and 270. The same was verified by overlaying the XRD of Sitagliptin and the corresponding Sitagliptin - excipient mixtures, the results showed lack of significant interaction and so it can be stated that their no incompatibility between Sitagliptin with citric acid, ascorbic acid and magnesium stearate. Furthermore, the FT-IR spectra of Sitagliptin shows significant bands at 3324.50, 3049.85 and 1636.96 cm-1 which correspond to amine functional group, aromatic C-H stretching and amide C=O group, these significant and characteristic peaks remain unchanged with all the excipients studied which confirms that there is no significant interaction between Sitagliptin and the excipients which are considered in this particular study.
The results demonstrated the suitability of DSC as a quick screening tool of candidate excipients at the early stages of a formulation design. Although thermal effects recorded at elevated temperatures must be interpreted cautiously and may not be always relevant at ambient conditions, DSC provides useful indications of the potential problems, so that an excipient can be rejected, or if it is considered indispensable, the nature of interactions with the active ingredient can be investigated in depth. In the case of Sitagliptin, compatibility with various excipients like croscarmellose, MCC, pregelatinized Starch, ascorbic acid, citric acid and magnesium stearate was demonstrated, as well as a facile transformation of dehydrated Sitagliptin to monohydrate in some mixtures. On the other hand, drug stability was strongly affected by the presence of tartaric and ascorbic acids, as reflected by the profound modifications of thermal profiles in the respective mixtures. The marked interaction in ground mixtures with magnesium stearate resulting in loss of melting endotherm of Sitagliptin was due to a heating-induced drug amorphization rather than to chemical degradation, as confirmed by the X-ray diffraction patterns. X-ray powder Diffractometry is, therefore, a valuable technique to support the DSC results in preformulation studies.
The authors wish to thank the management of United States Pharmacopeia-India Private Limited group for supporting this work. The authors are indebted to NIPER-Hyderabad, for providing the support and encouragement to carry out this work and S. Shanti Kumar is grateful to NIPER for providing fellowship. We would also like to thank colleagues in separation science division of Analytical Research of United States Pharmacopeia- India Private Limited for their cooperation in carrying out this work.