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“DEVLOPMENT AND VALIDATION OF SPECTROSCOPIC AND CHROMATOGRAPHIC METHODS FOR SIMULTANEOUS ESTIMATION OF ANTI ANXIETY DRUGS ALPRAZOLAM AND MELATONIN” SYNOPSIS FOR M. PHARM DISSERTATION SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BENGALURU, KARNATAKA BY M. THOMSON I M. PHARM DEPARTMENT OF PHARMACEUTICAL ANALYSIS PES COLLEGE OF PHARMACY BENGALURU-560050 UNDER THE GUIDENCE OF DR. NAGARAJ PROF & HEAD DEPARTMENT OF PHARMACEUTICAL ANALYSIS (2013-14) RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BENGALURU, KARNATAKA. ANNEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the candidate M.THOMSON and address: Department of Pharmaceutical Analysis, PES College of Pharmacy, 50 Feet Road, Hanumanthanagar, BSK I-Stage, Bengaluru-560050. Permanent Address S/O M.Thomas Jaya Kumar, Flat no.401, Hanuman Residency, Srinivas Nagar Colony, Hanamakoda, Dist: Warangal, Andhra Pradesh. 500037. 2. Name of the institution: PES College of Pharmacy 50 Feet Road, Hanumanthanagar, BSK I- Stage, Bengaluru -560050 3. 4. Course of study and MASTER OF PHARMACY IN subject: PHARMACEUTICAL ANALYSIS Date of the admission: 20/11/2012 5. Title of the topic: “DEVLOPMENT AND VALIDATION OF SPECTROSCOPIC AND CHROMATOGRAPHIC METHODS FOR SIMULTANEOUS ESTIMATION OF ANTI ANXIETY DRUGS - ALPRAZOLAM AND MELATONIN” 2 6. BRIEF RESUME OF THE INTENDED WORK: 6.1 Need for the study: General Discussion : The neurocircuitry of anxiety has been postulated to arise from the amygdala, the brain area that registers the emotional significance of environmental stimuli and stores emotional memories. The efferent pathways from the central nucleus of the amygdala travel to a multiplicity of critical brain structures, including the parabrachial nucleus (resulting in dyspnea and hyperventilation), the dorsomedial nucleus of the vagus nerve and nucleus ambiguous (activating the parasympathetic nervous system), and the lateral hypothalamus (resulting in SNS activation). Anxiety is a normal reaction to stress and can actually be beneficial in some situations. For some people, however, anxiety can become excessive. While the person suffering may realize their anxiety is too much, they may also have difficulty controlling it and it may negatively affect their day-to-day living. There are many types of anxiety disorders that include panic disorder, obsessive compulsive disorder, post-traumatic stress disorder, social anxiety disorder, specific phobias, and generalized anxiety disorder.(1) Causes of Anxiety Disorders:-(2) The exact cause of anxiety disorders is unknown; but anxiety disorders -- like other forms of mental illness are not the result of personal weakness, a character flaw, or poor upbringing. As scientists continue their research on mental illness, it is becoming clear that many of these disorders are caused by a combination of factors, including changes in the brain and environmental stress. Like certain illnesses, such as diabetes, anxiety disorders may be caused by chemical imbalances in the body. Studies have shown that severe or long-lasting stress can change the balance of chemicals in the brain that control mood. Other studies have shown that people with certain anxiety disorders have changes in certain brain structures that control memory or mood. In addition, studies have shown that anxiety disorders run in families, which means that they can be inherited from one or both parents, like hair or eye color. Moreover, certain environmental factors -- such as a trauma or significant event -- may trigger an anxiety disorder in people who have an inherited susceptibility. Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam is commonly used and FDA approved for the medical treatment of panic disorder, and anxiety disorders, such as generalized anxiety disorder (GAD) or social anxiety disorder (SAD). Alprazolam is available for oral administration in compressed tablet (CT) and extended-release capsule (XR) formulations. 3 Alprazolam possesses anxiolytic, sedative, hypnotic, skeletal muscle relaxant, anticonvulsant, and amnestic properties. Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy. The FDA label advises that the physician should periodically reassess the usefulness of the drug. Drug profile: ALPRAZOLAM:Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam is commonly used and FDA approved for the medical treatment of panic disorder, and anxiety disorders, such as generalized anxiety disorder (GAD) or social anxiety disorder (SAD). Chemical profile: N N N N Cl ALPRAZOLAM IUPAC name: 8-chloro-1-methyl-6-phenyl-4H-[1, 2, 4] triazolo [4, 3-a][1,4] benzodiazepine Empirical Formula: - C17H13Cl N4 Molecular Weight: - 308.77 Solubility in water: - 0.11 g/L (250C) Nature: Alprazolam is a white to almost white powder. Solubility: water solubility at 40 mg/L at pH 7; 12 mg/ml at pH 1.2 Availability: Each alprazolam tablet for oral administration contains 0.25,0.5 or 1mg of alprazolam 4 Pharmacodynamics: - (3) Alprazolam, a benzodiazepine, is used to treat panic disorder and anxiety disorder. Unlike chlordiazepoxide, clorazepate, and prazepam, alprazolam has a shorter half-life and metabolites with minimal activity. Like other triazolo benzodiazepines such as triazolam, alprazolam may have significant drug interactions involving the hepatic cytochrome P-450 3A4 isoenzyme. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis. Unlike other benzodiazepines, alprazolam may also have some antidepressant activity, although clinical evidence of this is lacking. In treatment of Anxiety disorders: - (4) Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy. The FDA label advises that the physician should periodically reassess the usefulness of the drug. In the US alprazolam is FDA-approved for the management of anxiety disorders or the short-term relief of symptoms of anxiety. Anxiety associated with depression is responsive to alprazolam. Demonstrations of the effectiveness by systematic clinical study are limited to 4 months duration for anxiety disorder. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety. Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting. Pharmacology:- (5 & 12) There is preclinical and clinical evidence suggesting that one neural mechanism responsible for antipanic efficacy is a reduction in brain noradrenergic function. Alprazolam, a triazolobenzodiazepine, has been demonstrated to have antipanic properties; however, to our knowledge, its effects on noradrenergic function have not been established. To assess whether alprazolam alters noradrenergic function, the effects of alprazolam on baseline plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and yohimbine-induced increases in plasma MHPG level, anxiety-nervousness, blood pressure, and somatic symptoms were studied in 14 patients with agoraphobia and panic disorder. Long-term alprazolam treatment significantly reduced plasma MHPG baseline and blunted the yohimbine-induced increases in plasma MHPG, anxiety-nervousness, and sitting systolic blood pressure. These observations suggest that 5 the antipanic mechanism of action of alprazolam may be due in part to an interaction between benzodiazepine-sensitive and noradrenergic neural systems.(1) Adverse effects:- (6) depressed mood, thoughts of suicide or hurting yourself, unusual risk-taking behavior, decreased inhibitions, no fear of danger; confusion, hyperactivity, agitation, hostility, hallucinations; feeling like you might pass out; urinating less than usual or not at all; chest pain, pounding heartbeats or fluttering in your chest; uncontrolled muscle movements, tremor, seizure (convulsions); or Jaundice (yellowing of the skin or eyes). MELATONIN:- (7) Melatonin is a hormone found naturally in the body. Melatonin used as medicine is usually made synthetically in a laboratory. It is most commonly available in pill form, but melatonin is also available in forms that can be placed in the cheek or under the tongue. This allows the melatonin to be absorbed directly into the body. The hormone melatonin is the primary controller of circadian (day/night) biorhythms. HN O O N H MELATONIN Chemical profile:IUPAC Name: N-[2-(5-methoxy-1H-indol-3-yl) ethyl] acetamide Empirical Formula: C13H16N2O2 Molecular Weight: 232.27834 6 Nature: Melatonin is a white amorphous powder. Solubility: H2O: soluble0.1 mg/ml; ethanol: soluble8 mg/ml. Availability: Melatonin is available as melatonin powder or as 1mg, 3mg, and 5mg tablets. Pharmacodynamics: -(8) Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions. In treatment of anxiety disorders:- (9) Melatonin is used in treating anxiety disorders .Melatonin is also used for the inability to fall asleep (insomnia); delayed sleep phase syndrome (DSPS); insomnia associated with attention deficithyperactivity disorder (ADHD); insomnia due to certain pressure medications called beta-blockers; and sleep problems in children with developmental disorders including autism, cerebral palsy, and retardation. It is also used as a sleep aid after discontinuing the use of benzodiazepine drugs and to reduce the side effects of stopping smoking. Pharmacology:- (10) Melatonin exerts its effects through activation of at least two high-affinity G-protein-coupled receptors, MT1 and MT2. These are unique receptors as they show distinct molecular structures, pharmacological characteristics and chromosomal localization. The MT1 and MT2receptors are 350 and 362 amino acids long respectively, with calculated molecular weights of 39–40 kDa. MT1 and MT2melatonin receptors signal by coupling to heterotrimeric G proteins formed by α, β and γ subunits. Activation of these receptors promotes dissociation of G proteins into α and β, γ dimers, which interact with various effector molecules involved in the transmission of cell signaling. Effector systems involved in MT1 and MT2 melatonin receptor signaling through G-protein coupling include adenylyl cyclase, phospholipase C, phospholipase A2, potassium channels and potentially guanylyl cyclase and calcium channels. 7 Tissues endowed with fully characterized functional MT1 and MT2 melatonin receptors include the retina, brain, suprachiasmatic nucleus, pars tuberalis, ovaries, cerebral and peripheral arteries, kidney, pancreas, adiposities and immune cells. ADVERSE EFFECTS:- (11) The most common melatonin side effects include: Daytime sleepiness Dizziness Headaches Other, less common melatonin side effects might include abdominal discomfort, mild anxiety, irritability, confusion and short-lasting feelings of depression. ALPRAZOLAM IN COMBINATION WITH MELATONIN:Melatonin is a hormone produced by the body that regulates your sleeping and waking patterns. It is also available as a supplement and works as an antioxidant. Melatonin supplements are used to treat insomnia, a common symptom of anxiety. Anxiety can interfere with your ability to fall asleep or cause you to toss and turn throughout the night. According to a study published in the January 2011 issue of "Clinical Medical Research and Opinion," sleep latency, sleep quality and quality of life improved among participants aged 18 to 80 who took prolonged-release melatonin over a three-week period. Alprazolam is an anti-anxiety medication that is used to treat anxiety disorders as well as panic disorder, and may be prescribed for some cases of depression. It is a strong, habit-forming medication and is not prescribed to alleviate day-to-day anxiety or stress. The starting dosage is typically 0.25 mg or 0.5 mg per day and may be gradually increased up to 4 mg daily. So, this combination of alprazolam along with melatonin can be preferred for the treatment of the anxiety disorders. This drug combination of alprazolam and melatonin is readily available in the market. Interactions: Melatonin can have negative side effects as a result of interaction with a number of other types of medication. For example, caution should be taken when taking melatonin along with psychotropic medications such as antidepressants, antipsychotics or benzodiazepines, such as alprazolam. It can be dangerous when taken in combination with blood pressure medications or blood thinners. Alprazolam can interact with other psychotropic drugs, anticonvulsants and antihistamines that also depress the central nervous system. So, these drugs must be used only as directed by the physician. (13) Literature survey reveals that, Alprazolam and Melatonin are both official in of the pharmacopoeias 8 like IP, BP, USP and European pharmacopoeia and it was found that above mentioned anti- anxiety drug was estimated alone or in combination with other drugs by various analytical methods like UV visible spectrophotometer (14, 15 & 16), HPLC (17, 18, 19 & 20), HPTLC–UV (21), and spectrofluorimetric (22) methods were reported. In view of need for a suitable method for routine analysis in formulation, an attempt has been made to develop simple, efficient spectroscopic and chromatographic methods for the simultaneous estimation of both Alprazolam and Melatonin in pharmaceutical dosage form. .Analytical validation is the corner stone of process validation. Without a proven measurement system it is impossible to confirm whether the manufacturing process has done what it purport to do. Hence, there is a need to validate the new methods developed. 6.2 REVIEW OF THE LITERATURE: Gupta M, et al. have published a review article on a reverse phase high performance liquid chromatography method for simultaneous estimation of melatonin, carbamazepine epoxide and carbamazepine simultaneously in serum. Makwana DH, Patel PB have published review article on development and validation of spectroscopic methods for simultaneous estimation of alprazolam and mebeverine hydrochloride in bulk drug and pharmaceutical dosage form. Ayesha SS, et al. have published a review article on method development &validation for the simultaneous estimation of zolpidem and melatonin in pharmaceutical dosage form by using rphplc. Priscilla K, et al have published a review article on validated liquid chromatographic method for simultaneous estimation of melatonin and zolpidem tartarate in tablet dosage form. Darwish HW, et al. have published a review article on New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]- ethyl}acetamide: a contaminant in commercial melatonin preparations. Kuchekar BS, et al. have published a review article on spectrophotometric estimation of melatonin and pyridoxine hydrochloride in combined dosage forms. Guo NC, et al have published a review article on Chemiluminescence determination of melatonin and some of its derivatives using potassium permanganate and formaldehyde system. 9 Kiran K, et al. have published a review article on UV spectrophotometric method for the estimation of alprazolam in tablet dosage form. Magdalena WK, et.al have published a review article on Quantitative determination of melatonin in Lamium album flos. Sharma S, et.al have published a review article on Method development and validation of UV spectrophotometric method for alprazolam in pharmaceutical dosage forms using ferric chloride and indigo carmine. Madhur G, et.al have published a review article on reverse phase high performance liquid chromatography method for simultaneous estimation of melatonin, carbamazepine epoxide and carbamazepine simultaneously in serum. Venkateshwarulu, et.al have published a review article on Development of HPTLC–UV absorption densitometry method for the analysis of alprazolam and sertraline in combination and its application in the evaluation of marketed preparations. Sagar B, et.al have published a review article on A novel HPTLC method for simultaneous determination of alprazolam and methyl paraben in tablet dosage form. 6.2 OBJECTIVES OF THE STUDY: In the proposed work attempts shall be made to: Develop new analytical methods and validation for the simultaneous estimation of Alprazolam and Melatonin. Validate the proposed method in accordance with ICH and Pharmacopoeial guidelines for the intended analytical application. Apply the proposed methods for analysis of Alprazolam and Melatonin as API and in dosage form. 10 7. MATERIALS AND METHODS: 7.1 Source of data: Literature survey was done at P.E.S. College of Pharmacy using Internet facilities (RGUHS HELINET) and at Library. Reference from library at RGUHS, Bangalore. Indian Institute of Sciences, Bangalore. Department of Drug testing Laboratories, Bangalore. 7.2Method of collection of data: Simultaneous estimation and analytical method development on Alprazolam and Melatonin drug shall be carried out in PES COLLEGE OF PHARMACY. The analytical methods will be developed by using instruments like UV visible spectrophotometer, HPLC, HPTLC instrument. The data so obtained is treated statistically to determine the compliance of the experimental result as per ICH and Pharmacopoeial guidelines and for the routine use of the developed analytical methods in industry. JOURNALS: 1. Indian Journal of Pharmaceutical Sciences. 2. Journal of Chromatography A 3. Journal of Chromatography B. 4. Asian Journal of Pharmaceutical and Clinical Research. 5. Eurasian Journal of Pharma Chemistry. 6. International Journal of Pharma Research and Development. 7. Journal of Medical Microbiology. 8. Journal of Young Pharmacist. 9. World Journal of Pharmaceutical research. 10. International Journal of Pharmacy and Pharmaceutical sciences. 11. International Journal of Clinical Pharmacology and Toxicology. 11 7.3. DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? NOT APPLICABLE 7.4. HAS ETHICAL CLEARENCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3? NOT APPLICABLE. 8. REFERENCES: 1. http://www.health.am/psy/more/pathophysiology_of_anxiety/ 2. http://www.webmd.com/anxiety-panic/guide/mental-health-anxiety-disorders?page=2 3. http://neurolex.org/wiki/Category:Alprazolam 4. http://en.wikipedia.org/wiki/Alprazolam 5. http://www.ncbi.nlm.nih.gov/pubmed/2859008 6. http://www.drugs.com/sfx/xanax-side-effects.html 7. http://www.nlm.nih.gov/medlineplus/druginfo/natural/940.html 8. http://www.drugbank.ca/drugs/DB01065 9. http://www.nlm.nih.gov/medlineplus/druginfo/natural/940.html 10. http://www.medscape.com/viewarticle/780687_11 11. http://www.mayoclinic.com/health/sleep-aids/SL00016/NSECTIONGROUP=2 12. Charney D. Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment. Arch Gen Psychiatry. 1985;42(5):45867. 13. Scientific discussions. 14. Sharma M. Method development and validation of UV spectrophotometric method for alprazolam in pharmaceutical dosage forms using ferric chloride and indigo carmine. European journal of applied sciences. 2011; 3(3):81-5. 15. Kuchekar B, Thakkar S, Hiremath M, Cothe P, Shinde D. spectrophotometric estimation 12 of melatonin and pyridoxine hydrochloride in combined dosage forms. Indian journal of pharmaceutical sciences. 2002;64(2):158-60. 16. Kiran KA, Mohan KA, Sudheer M, Sai RK, Ramalingam P. UV spectrophotometric method for the estimation of alprazolam in tablet dosage form. International journal of chemtech research. 2011;3(1):161-4. 17. Magdale N. Quantitative determination of melatonin in Lamium album flos Herbapolonica. 2008; 54(7). 18. Gupta M. A reverse phase high performance liquid chromatography method for simultaneous estimation of melatonin, carbamazepine epoxide and carbamazepine simultaneously in serum. Indian J Physiol Pharmacology. 2006;50(4):427-30. 19. Ayesha SS, Rajkumar B, Bharadwaja B, Priyanka S, Ramachandrudu B, Bhagyawati M, et al. Method development and validation for simultaneous estimation of zolpidolem and melatonin in pharmaceutical dosage form by using RP-HPLC. IJPWR. 2012; 3(1). 20. Guo N. Chemiluminescence determination of melatonin and some of its derivatives using potassium permanganate and formaldehyde system. Analytical & Bioanalytical Chemistry. 2003; 376(6):873. 21. Venkateshwarulu. Development of HPTLC–UV absorption densitometry method for the analysis of alprazolam and sertraline in combination and its application in the evaluation of marketed preparations Journal of Chromatographic Science. 2007; 45:537-9 22. Darwish H. New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetyl amino) ethyl]-5-methoxy-1H-indol-2-yl} methyl)-5methoxy-1H-indol-3-yl] - ethyl} acetamide: a contaminant in commercial melatonin preparations. Chem Cent J. 2012;6(1):36. 13 9. Websites: http://www.sciencedirect.com http://www.ingentaconnect.com http://www.rguhs.ac.in http://www.pubmed.com http://www.medline.com http://www.chemindustry.com http://www.google.com 14 10. Signature of the candidate (M. Thomson) Forwarded for Approval 11. Remarks of the guide 12. Name and Designation of Dr. Nagaraj Professor & Head 12.1 Guide Department of Pharmaceutical Analysis, PES College of Pharmacy, Hanumanthanagar, Bengaluru-560050 12.2 Signature Dr. Nagaraj Professor & Head Department of Pharmaceutical Analysis, 12.3 Head of the department PES College of Pharmacy, Hanumanthanagar, Bengaluru-560050 12.4 Signature 13. Remarks of the Chairman and Forwarded for Approval Principal Prof. Dr. S. Mohan Principal & Director, 13.1 Signature PES College of Pharmacy, Hanumanthanagar, Bengaluru-560050 15 16