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Department of Pharmaceutical Chemistry, R.
Harry G. Abdullah A. Al-Badr Gerald S. Brenner Glenn A. Brewer Harry G. Brittain Klaus Florey George A. All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher.
Academic Press, Inc. California I United Kingdom Edition puhlished hy. Academic Press Limited Oval Road. Ezzur M. Vijay K. Sahota, Hoffmann-La Roche, Inc. Michael Wall, Alcon Laboratories, Inc. The profiling of the physical and analytical characteristics of drug compounds remains as important today as it was when the Analytical Profiles series was first initiated. The compilation of concise summaries of physical and chemical data, analytical methods, routes of compound preparation, degradation pathways, and the like, is a vital function to both academia and industry.
The expansion of the series mission to include profiles of excipient materials reflects the realization that all aspects of a drug formulation need to be fully specified. It is no longer sufficient to consider excipients as merely representing the inactive portion of a dosage form. In the future, it is likely that more complete chemical and physical characterization work will have to be performed, which will in turn increase the existing body of knowledge.
For the sake of the pharmaceutical community, this accrued information will be summarized in a series of excipient profiles. The extensive chapter on Povidone contained in this volume is an indication of how detailed these excipient profiles can be. The success of the Analytical Profiles series will continue to be based on the contributions of the chapter authors, and on the quality of their work.
We seek to profile new drug compounds as they become marketed, but also wish to profile important older compounds which have somehow escaped attention. Updates on compounds profiled earlier in the series are always welcome, especially once new and significant information has become available as a result of the continuing advances in the field. A complete list of available drug and excipient candidates is available from the editor. We look forward to hearing from new and established authors, and to working with the pharmaceutical community on Analytical Profiles o Drug Substances and Excipients.
Pharmacokinetics and Metabolism 6. I n t h e e a r l y s, Roughton 1 discovered t h e existence i n erythrocytes of an enzyme which promotes t h e hydration o f carbon d i o x i d e and dehydration o f carbonic acid.
The enzyme was found t o be carbonic anhydrase. Since then, t h e presence of carbonic anhydrase has been demonstrated i n p r a c t i c a l l y every physiological b a r r i e r where i o n exchange occurs, e.
I n , a series o f unsubstituted h e t e r o c y c l i c sulfonamides were synthesized. Thus, acetazolamide was f i r s t used by physicians i n as a d i u r e t i c. Acetazolamide i s indicated f o r centrencephal i c e p i l e p s i e s p e t i t malt unlocalized seizures , chronic simple open angl e glaucoma, secondary glaucoma, and preoperatively i n acute angle closure glaucoma where delay o f surgery i s desired i n order t o lower i n t r a o c u l a r pressure 8.
Acetazolamide i s used as an adjuvant i n t h e treatment o f c e r t a i n dysfunctions of t h e central nervous system i n which cerebral spinal f l u i d pressure i s increased, e.
However, i t has been replaced by newer d i u r e t i c s f o r these indications. Acetazolamide i s n o t a mercurial d i u r e t i c. Rather, i t i s a nonbacteriostatic sulfonamide possessing a chemical s t r u c t u r e and pharmacol og ical a c t i v i t y d ist in c t l y d if f erent from t h e b a c t e r i o s t a t i c sulfonamides. Among t h e enormous number o f sulfonamides t h a t have been synthesized and tested, acetazolamide has been studied most extensively as an i n h i b i t o r o f carboni c anhydrase.
Acetazolamide i s 2-acetylamido-1,3,4-thiadiazole-5sul fonamide; N- 5-Sul famoyl-l,3,4-thiadiazol e-Z-yl. The structure of acetazolamide is shown in Figure 1.
A fine, white-to-faintly-yellowish-white, odorless, bitter crystalline powder. The u l t r a v i o l e t absorbance o f acetazolamide scanned from t o nm i s presented i n F i g u r e 2. The wavelength o f maximum absorbance i s a t n The concentration o f acetazolamide i n saturated s o l u t i o n s o f various pH values i s shown i n F i g u r e 3 However, degradation increases manyfold on t h e basic side, which precludes measurement o f e q u i l i b r i u m s o l u b i l i t y above pH 8.
Sol vents: Table 1 shows t h e s o l u b i l i t y o f acetazolamide i n various common1y used pharmaceutical solvents. There i s an increase i n aqueous s o l ubi 1it y o f acetazol ami de upon t h e a d d i t i o n o f cosolvents. According t o t h e equation derived by Yalkowski e t al. G1 ycerol ;. Acetazolamide has two polymorphic forms Forms A and The solubility and dissolution rate of Form B is about 1.
The transition temperature obtained by solubility measurement is 78"C, and the heats of transition AHtrans calculated by solubility measurement and by differential scanning calorimetry are 2 6.
It is therefore presumed, following Aguiar and Zelmer, that acetazolamide polymorphic forms do not significantly affect bioavailability. The kinetics of isothermal transition from Form A to Form B at high temperature follows the mechanism of random nucleation with first-order kinetics.
The activation energy for this tran ition as derived from Arrhenius plots is kJ. The results from the scanning electron microscope indicate that the crystal shape of acetazolamide during isothermal transition from Form A to Form B does not change significantly Form B gives only one endothermic peak at OC corresponding to the melting point which is accompanied by decomposition as i ndi cated by the exothermic peak.
Infrared spectra of acetazol amide's two polymorphic forms are shown in Figure 7 The spectrum of Form A is different from that o f Form B. In particular, Form A shows. The me1t i ng p o i n t range o f acetazol ami de is OC, accompanied by decomposition. D i f f e r e n t i a l Scanning Calorimetry DSC curves o f acetazolamide's two polymorphic forms a r e shown i n F i g u r e 6 Form B g i v e s o n l y one endothermic peak a t OC corresponding t o t h e m e l t i n g p o i n t which i s accompanied by decomposition as i n d i c a t e d by t h e exothermic peak.
Infrared spectra of acetazolamide's two polymorphic forms are shown i n Figure 7 The spectrum of Form A is different from that of Form 6. In particular, characteristic absorption peaks in the and Form B gives a specific peak at about cm-.
The X-ray powder diffraction patterns of the two polymorphic forms a r e shown i n Figure 8 O the other hand, n Form B gave the h i g h e s t diffraction pattern a t The NMR spectra of acetazolamide contains broad peaks centered a t cps 6 The 1 N NMR spectra of acetazolamide was measured in 5 hexadeuteriodimethyl sufoxide. I n i t i a l l y protondecoupled ad protoncoupled spectra of the nitrogens bearing hydrogens acetylacetonate Cr [Cr acac was added t o sol ution because the Cr acac 3 considerab y shortens the relaxation tim and thus enables f a s t e r pulse r e p e t i t i o n.
The changes of f S N chemical s h i f t s induced by the addition of t h i s able 3 l i s t s laxation reagent i s small usually 4 ppm N chemical s h i f t s and coupling constants ; 15N of H.
Several assay methods f o r acetazolamide have been reported, such as u l t r a v i o l e t absorption spectroscopy , p o l oragraphy 34 , e l e c t r o n capture gas-1 iq u i d chromatography 36 , high-performance 1i q u i d chromatography , amperometric determination using a s e s s i l e mercurydrop d e t e c t o r 45 , and nuclear magnetic resonance I n t e r f e r i n g absorbance due t o e x c i p i e n t s i n pharmaceutical formulations a f f e c t s t h e accuracy o f t h e spectrophotometric method.
Acetazolamide can be assayed i n a polarographic c e l l t h a t i s immersed i n a water bath regulated a t 25 k 0. A mercury-drop electrode should b e immersed i n a s u i t a b l e polarograph, and the polarogram recorded from 0. Diffusion current i s recorded a t A method of determining acetazolamide by reductive amperometry w i t h flow injection using a s e s s i l e mercury-drop electrode i s reported 4 5 4 Acetazolamide was determined i n the range of mcg m l a t Acetazolamide can be assayed using an NMR spectrometer equipped w i t h a variable temperature probe having a six-turn insert.
Spectra were scanned a t a probe temperature of 42'C. Table 4 describes assays published in the literature. U1 trasphere 0. The decomposition o f acetazolamide follows a firstorder kinetics Figure The pH-rate profile curve Figure 11 is V-shaped, which indicates specific acid-base catalysis. The slopes o f the pH-rate profile curve for the acidic and alkaline solutions is The pH of maximum stability i s 4 46, Figure 1 : First-order plots o f acetazolamide at different 0 pH values.
Results of frozen samples thawed i n a microwave oven a r e s i m i l a r t o those samples thawed using tap water 4 8. Thawing i n a microwave can be completed i n l e s s than two minutes. The higher-temperature data. The p o s i t i v e enthalpy value determined using Equation 1 i n d i c a t e s endothermic r e a c t i o n. The increase i n enthalpy as pH values a r e increased i n d i c a t e s higher heat contents o f t h e s o l u t i o n a t higher pH values.
The change i n t h e entropy values from The kobs values a r e very similar w i t h different ionic strengths. T h i s indicates t h a t it is the unionized acetazolamide which reacts w i t h e i t h e r H or OH-. The hydrolysis of acetazolamide may b e represented as f 01 1ows :.
Assuming the k o t o be 0. Using the kobs valuf of 0. The stabi 1 i t y of acetazolamide i n pure unbuffered sol vents 1 i ke propyl ene glycol , pol yethyl ene glycol , and water i s not optimum, probably because of the higher pH values of these solutions a t which acetazolamide i s not stab1e.
Dexamethasone is used in pediatrics mainly for treatment of croup and bronchopulmonary dysplasia. Commercially available pediatric oral formulations include inadequate excipients for this population. When there are only commercially available oral dosage forms for adults, a formulation is prepared to reduce the dose by manipulation of authorized tablets or injectable dosage forms. This practice most of times is made without the quality and control that process requires. The aim of this study is to propose a formulation secure and suitable for pediatrics by the use of a Standard Operating Procedure that ensures its quality. Design of two formulations was performed with lowest number and amount of excipients suitable for pediatrics, avoiding use of dexamethasone salts and preservatives. An accurate and precise analytical method and a methodology for analyzing uniformity of doses were developed.
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Embed Size px x x x x Nomenclature I. Methods of Analysis 4. Stability 5. Mesalamine is obtained as a tan to pink crystalline powder, whose individual crystals exhibit a needle-like morphology.
Clomiphene citrate. Mebeverine hydrochloride. Metformin hydrochloride. Tranylcypromine sulfate.
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Indrayanto, A. Syahrani, Mugihardjo, A. Rahman, Soeharjono, W. Tanudjojo, S. Susanti, M. Yuwono, and S.
Harry G. Abdullah A. Al-Badr Gerald S. Brenner Glenn A. Brewer Harry G.
Analysis and Control Section, Academy of Pharmaceutical. Sciences. Includes The compilation ofdnnlyticcil Profiles of Drug Szibstunces to supplement the information a Jeol PX-loo spectrometer operating at FlHz. The samples.
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Analytical Profiles of Drug Substances and Excipients. Edited by Harry G. Brittain. Volume 25, Page ii: Download PDF. select article Front Matter.Holly D. 20.03.2021 at 14:22
The results show that two multivariate techniques, principal component analysis PCA and cluster analysis CA , can be successfully used for interpretation of TG traces, while the TG is used alone as a screening technique to assess compatibility.Venus M. 23.03.2021 at 22:56
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