New polymorph of armodafinil and its stability studies

Transcription

1 Research Article New polymorph of armodafinil and its stability studies Runjhun Tandon 1, Nitin Tandon 1 *, Raakhi Gupta 2, Neelima Gupta 3 ABSTRACT Aim: The study of polymorphism in drugs is very important and is an integral part of drug development in present days. In fact, a detailed drug study helps to resolve problems such as drug solubility and drug formulation techniques in drug manufacturing processes. The individual of drug polymorphism has received extensive academic and industrial attention. The regulatory requirements for filing new drug application (NDA) and abbreviated NDA of a particular dosage form are so stringent that pharmaceutical companies are bound to study polymorphs along with their bioavailability and stability. The aim of the research is to identify new polymorph of armodafinil. Materials and Methods: A new polymorph of armodafinil one of the sleep awakening drugs in the market is synthesized and characterized using pxrd, DSC, TGA and its stability studies. KEY WORDS: Armodafinil, Crystalline, Polymorph, Sleep awakening, Stability INTRODUCTION Polymorphism is derived from Greek word, Polus means many and morph, means shape. In other words, it is defined as the ability of a substance to exist in two or more crystalline phases that have different arrangements or conformations of the molecules in a crystal lattice. [1] In case the difference is because of packing of the molecules, it is termed as packing polymorphism, and if it is due to differences in conformation, it is called conformational polymorphism. [2] The different arrangements of atoms within the unit cell of various polymorphs can have a profound effect on the properties of the final crystallized compound. [3] The history of polymorphism dates back to the year 1812 when Napoleon Bonaparte and his soldiers in the army wore highly decorated and shiny buttons on the uniform. The β-form of tin is white and stable at 18 C while the α-form is gray and stable below this temperature. Shining buttons of tin made in summers changed to dirty gray in winters. This change at that time was considered as God s wrath. However, today, the scientific reason for crumbling of buttons can be attributed to polymorphic transition. The change in crystal structures of the same chemical compound is called polymorphic transformation and is exhibited by a number of inorganic, biological, and Access this article online Website: jprsolutions.info ISSN: pharmaceutical compounds. In fact, polymorphism plays an important role in those areas of chemical research where the full characterization of material has a pivotal role in determining its ultimate use, for example, pharmaceutical, pigment, agrochemical, explosive, and fine chemical industry. In case of elements, polymorphism is termed as allotropy. [4] Graphite and diamond are one of the classic examples of allotropism in carbon. Another example of allotropy is the existence of phosphorous (P 4 ) in cubic (white), monoclinic (purple), and orthorhombic (black) forms (Figure 1). In addition to elements, inorganic minerals also exhibit polymorphism, for example, ZnS is known in the forms referred to as wurtzite and sphalerite. [5] Polymorphs of CaCO 3 are calcite, aragonite, and valerite. Polymorphism has also been reported in large biological molecules like protein molecules, arising out of change in the conformation. [6] Lysozyme is an enzyme, which crystallizes in six different forms due to the difference in water content, amount of anions, and packing arrangement. Besides proteins, amino acids have also been reported to show change in crystal structure, for example, L-glutamic acid exists in two different morphs a and a which have different shapes - rhombic and needle-like. [7] It has been reported that change in polymorph of a drug has profound effect on its solubility, dissolution 1 Department of Chemistry, Lovely Professional University, Jalandhar-Delhi, Phagwara, Punjab, India, 2 Department of Chemistry, IIS University, ICG Campus, GurukulMarg, SFS, Mansarovar, Jaipur, Rajasthan, India, 3 Department of Chemistry, University of Rajathan, JLN Marg, Jaipur, Rajasthan, India *Corresponding author: Nitin Tandon, Lovely Professional University, Phagwara, Punjab, India. tandonnitin12004@gmail.com Received on: ; Revised on: ; Accepted on: Journal of Pharmacy Research Vol 11 Issue

2 rate, and bioavailability. During batch crystallization, often solvent molecules get trapped within the crystal lattice resulting in the formation of a solvate. The solvate may have high organic volatile contents entrapped that might not match with the Q3 guidelines of the FDA. [8] Therefore, the study of polymorphism in pharmaceutical compounds is very important and is an integral part of drug development in present days. In fact, a detailed drug study helps to resolve problems such as drug solubility and drug formulation techniques in drug manufacturing processes. The stability of polymorph is one of the main questions to determine the expiry date of the final formulated drug. Aguiar et al., [9,10] at Parke-Davis illustrated the effects of polymorphism on drug bioavailability and dissolution rates in the case of chloramphenicol palmitate, and since then, the individual of drug polymorphism has received extensive academic and industrial attention. The regulatory requirements for filing new drug application (NDA) and abbreviated NDA of a particular dosage form are so stringent that pharmaceutical companies are bound to study polymorphs along with their bioavailability and stability. The search for new polymorphs with novel properties is a fascinating though arduous task. New researchers are being made every day, and new insights are being gathered confirming the view of McCrone who quoted every compound has different polymorphic form and that, in general, the numbers of forms are known for a given compound is proportional to the time and energy Figure 1: Allotropy in phosphorous spent in research on that compound. The discovery of a new polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of that product. For example, in case of a polymorph with poor solubility, the formulation can be developed in a manner to minimize the effect of the polymorphism on dissolution and bioequivalence. If a metastable or amorphous form is being used in a drug, the suitable excipient can be chosen to improve the chemical stability of the drug. Armodafinil, the sleep awakening drug, is also known to show many polymorphic structures. It is the R enantiomer of Modafinil marketed by Cephalon. A total of 23 polymorphs are reported for armodafinil, maximum of which are solvates. [11-14] MATERIALS AND METHODS The solvents used were obtained from S.D fine chemicals and API, and its intermediates were obtained as gratis from MacLeods Pharma. A combination of different solvents was used to isolate a novel and crystalline morph of armodafinil. A synthesized sample of armodafinil was dissolved in dioxane and to the resulting solution; cyclohexane was added dropwise to precipitate the polymorph. The powder X-ray diffraction (PXRD) of the isolated material indicated it to be a new polymorph, which is referred to as Form R in this research article. RESULTS AND DISCUSSION The new morph of armodafinil isolated was characterized by PXRD, differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). The new form isolated Form R was found stable at a lower temperature, i.e., 5 C. The form degraded at room or higher temperature. An isolated form is a pure form but not a stable one at higher temperatures. PXRD of Form R The X-ray diffractogram of Form R is presented in Figure 2, and the 2θ values are corresponding to crystalline peaks observed in present case along with those reported for Form II are presented in Table 1. A comparison of the 2θ values shows that the peaks are distinct from the crystalline peaks of Form II. [14] Table 1: PXRD values of armodafinil samples Figure 2: Powder X-ray diffraction patterns of Form R Sample ID 2θ values Form R a 4.61, 4.70, 5.28, 10.20, 10.38, 10.55, 18.39, 19.47, 19.90, 24.10, 24.62, 28.19, Form II b 11.6, 15.4, 17.4, 17.7, 23.3, 24.8, 27.4, 28.9, 29.1, 29.8, 32.8, 34.3, 35.3, 35.9, 40.1, 47.7, 53.7 a By experimentation, b as reported in literature. [14] PXRD: Powder X ray diffraction Journal of Pharmacy Research Vol 11 Issue

3 Table 2: Stability data of Form R Time (month) 2θ values Peak intensity 5 C 25 C 45 C 70 C 1 st Month No change No change No change No change 3 rd Month No change 4.61, , 5.28, 11.6, 15.4, , 5.28, 11.6, 15.4, 17.4 Decreased 4 th Month No change 4.61, , 5.28, 11.6, 15.4, , 5.28, 11.6, 15.4, 17.4 Decreased 6 th Month No change 4.61, , 5.28, 11.6, 15.4, , 5.28, 11.6, 15.4, 17.4 Decreased Figure 3: Thermogram of Form R Figure 4: Differential scanning calorimetry curve of Form R 1200 Journal of Pharmacy Research Vol 11 Issue

4 a b Figure 5: (a and b) Powder X-ray diffraction patterns of Form R TGA of Form R Form R was further characterized by TGA. The thermogram of Form R is reproduced in Figure 3, which shows a weight loss of mg ( %) only. This weight loss is not substantial to support the presence of any solvate or hydrate in this form. TGA of Form II is not reported in literature. DSC of Form R The literature survey does not reveal any DSC data for the thermodynamically most stable Form II of armodafinil. The DSC obtained for Form R of armodafinil is reproduced in Figure 4, the endotherm starting at 163 C and forming a sharp peak at C confirms it to be a pure polymorph. Stability Studies of Form R Storage conditions In the stability study of Form R, the samples were packed in double polythene pack with aluminum foil and were stored for 6 months at 5 C, 25 C, 45 C, and Journal of Pharmacy Research Vol 11 Issue

5 a b Figure 6: (a and b) Powder X-ray diffraction patterns of Form R 70 C. The PXRD for each sample was recorded after 1 st, 3 rd, 4 th, and 6 th months. PXRD Data for Stability Study The X-ray diffractograms obtained for each sample at different time periods are reproduced in Figures 5 and 6, and 2θ values as a measure of stability data are represented in Table 2. At 5 C, no polymorphic transformation is indicated by the diffractogram up to 6 months. However, at 25 C, the characteristic peaks of Form R at 2θ 4.61 and 5.28 were found to be diminishing 3 rd month onward without the appearance 1202 of any new peak. However, at 45 C and 70 C new peaks at 2θ 11.6, 15.4, and 17.4 corresponding to Form II start appearing after 3 rd month in addition to the decrease in the intensity of peaks of Form R. Therefore, it may be inferred that the novel polymorph Form R is stable at the lower temperature. ACKNOWLEDGMENT Our special thanks to MacLeods Pharma for providing us the samples and helping us in the analysis of the prepared samples. Journal of Pharmacy Research Vol 11 Issue

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