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  • Assuring Quality of Drugs by Monitoring Impurities

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    Amanda Suárez Jaen
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    Assuring Quality of Drugs by Monitoring Impurities Article

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    21 visualizações9 páginas

    Assuring Quality of Drugs by Monitoring Impurities

    Enviado por

    Amanda Suárez Jaen
    Assuring Quality of Drugs by Monitoring Impurities Article

    Direitos autorais:

    © All Rights Reserved
    Baixe no formato PDF ou leia online no Scribd
    Sinalizar o conteúdo como inadequado
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    ‘Avatabe ontine at www sclancedirect com ores 32°C: i DRUG DEL! ‘2° ScienceDirect Reviews ——= ‘Adan Dr Denn Reviews $9(2007)3-11 noenannaselee Assuring quality of drugs by monitoring impurities Satinder (Sut) Ahuja * ‘hugo Conslans, 1061 Runge Court, Calaish, NC 28467, USA Received 14 January 2006; accepted 25 October 2006 Avlbie online 16 November 2006 a act To assure the quality of Potential sources of such Impuntios to provide production procedures, ‘drugs. impurities must be monitored care import to understand what constitutes an impurity and w identify ust be monitored cael ris important oundestan yan wo identify p mous: Seas analjal methods nee yb develop omar dan 1 generally deal Pron tuck for comperauive purposes. New impurities may be observed as changes are made in the synthesis, fomnuh A bit for improving them. At umes is necessary to oate and characterize an impurity when typhenated methods donot sa confirmation is necessary with an authentic mueral, Availability of an authentic material can also,allow, toxicological a anda for vane motor ea © 2007 Published by Eisevier BW. Kownis. Cosacienea 5 joe non, Cheat impunity: Degradation product; Drug pract: Dg substance: Isolation: Profiling; Selesve analytien! methodologies 241. Starang materials) 212. Intermediates 21.3. Penulumate intermediste 214. By-products ei 2.15. Transformation products 2.16. Interaction products 2.1.7, Related products . Ordinary impurities 5 Organic volatile impurities (OVIs) 2.3. ICH terminology < 23.1, Organic impunties 23.2. Inorganic impurities , fe LS PBS, Ore maetly eee cy teen ee, . ee ea * Campnteg aor Tent 1027 365 slop an Reply Penpecies ecalaess mabee na (0169-409X'S - see foot matter © 2007 Published by Elsevier BV. dos. 10 1046 nde 2006. 10,003 234. Residual solvents (Comments on vanous terminotogies 24.1, Chiral impurities Wentification and qualification thresholds of impurities Sources of impurities 4.1. Syothesis-elated impurities i eee S. Dgteartoel rae ieee ee 5. Seeman eases aoe Seana Pies jeear shared S13. Mass apeceomety ™ Seman met 5. Hyphenated methods 6. Impurity profiling 6.1. Sampies 10» profiled 62. Components seen in a profile 7. Isolating impurities. 8. Characterization of impurities 9. Acase study 9.1. HPLC methods 9.1.1 Achsral impurities 91.2. Chiral impurities 10. Cenelusions References S thy / Advanced Drag Delivers Reiens 2007) 1h Coe Soma menEN 216 10 1 10 re 1, Introduction Webster's dictionary defines impurity as something that is impure or makes someting else impure. An impure substance may be defined as follows: a subslance. of interest mixed or impregnated with gn fesidual solvents that may be found ‘may be found in the drug substance. OVIs are Benerally solvents uscd in the 5: Aha Advance Brug Deters Reviews 39 (2007) 3-11 yothesis or during formulation of the drug product. The Solvents have been classified as follows by ICH, Class 1 (to be avoided): benzene, carbon tetrachloride, 1,2-di- chloromethane, 1, t-dichloroethane, and |,1,l-trichlorvethane. Class Il (should be limited): acetonitrile, chloroform, ‘methylene chloride, *1.2richloroethane, 1,4-dioxane, and pyridine Class IT: jay torte potenti (PDE) of 30 mg or more Class IV: solvents for which adequate toxic data are not available and permitted daily exposure 231CHierminaloes, 23.1. Qrganic impuries ‘Starting matenals Process-rolated impurities Intermediates Degradation products. 2.3.2 Inorganic impurities Salts Catalysts Ligands Heavy metals or other residual metals 2.33. Other materials Filter aids Charcoal 2.3.4 pResiduat solvers Organic and inorganic liquids used during production and/or crystallization. 2.4, Comments on varicus terminologies “The mpunties shat may be present in the stating materials) can potentially be carried into the sctiveringredient of interest. And th pelate-t0.the.solvenly used during synthesis and the inert ingredients gexsipicys) used for formulation must also pe-cossidesed potential impurities that may be found in API or drug product. Jporgaaic impurities may also be found in corapendial articles. These ympuritis.zaay be as supple as.common. salt.or othar.compounds that. are controlled, such as digavyotnetalsgarsemoy etc. which can be introduced during va-ious synthetic steps. Potential reaction by-products, degradation products, and drug substance-excip- tent interactions must also be evaluated, All of these im- purities have the potential of being present in the final drug product. Of the various terminologies described above, the Intema- tional Conferenos.om fiarmonisation (ICH) provides a simple ‘leseuiionvon to edequatoly address various impurities that may be present in ph -produbts. However, all of these terminologies’ fail to adequately highlight that enantiomeric (chiral) gpusitias might warrant adclitional considerations. sia formu and a te en a ean a ane} se (S, a ull bu 24.1. Chiral impurities ane “Chiral amp wvo-the identical the same connectivity etween various {files hays. boon. observed. wat, ‘This, suggests_that_ciral_ puri carefully. and qualification dhreshotds of impurities isation addresses ‘The Inemaional Conference on Harmonisation questions relating to impurities as flows | substances and Q1A (R) sibility testing of mew drug substances products O3A (R) impurities in drug subsiances 30 impuries a au lae Q3€ impurities ents — Goa specications: test procedures and acceptance et for new drug substances and new drug products; chemica! substances ICH. guidelines for the identification and qualification threshold of impurities and degradation products are provided ingables?. “As canr-be seen from the data in Table 2, ICH treats the sgradatiog products slightly @ifferently than-impurities even tough for all intents and purposes the degradation products are impurities. : 4. Sources of impurities Discussed below are three important sources of impurities, 4.1, Synthesis-related impurities Impurities in @ drug substance or a new chemical entity (NCE) originate mainly during the synthetic process from raw materials, solvents, intermediates, and by-products. The raw Diatscials are generally manufactured to much ower-pucsty requirements than a drug substance. Hence, it is easy to understand why they can contain a number of components that can in tum affect the purity of the drug substance. Simalary, solvents used in the synthesis are hkely to contain 1 number of impurities that may range from trace levels significant amounts that can react with various chemicals used ie Tol fo ping inpres Maximus Repo ing eninton diy dowe trate tes Seto ‘Leas or equal an Sig baer lampiy oer omy se sayy, _‘(ihtiions) toner 0.05%, |S Ab / Advanced Dg Del ‘Thresol or eporing degradation produ n «new dug poduet Maxine ay due inthe synthesis to produce other impurities Intermediates are also not generally eld to the purity level of the drug Subsiance hence the remarks made for the raw materials apply. I isnot reasonably possible to theorize all by-products; as a result, any such products that may be produced in the synthesis would be hard o.manior. The “pot reactions,” ie, When the intennediates are not isolated, are convenient, economical, and timesaving; however, they raise havoc in terms of the generation. of impurties-because, a numberof ‘Eoctions ca ocour simultaneously. Incidentally this problem of numefous reactions occuring simultancously can be also encountered in single reactions where intermediate is isolated The final termediate is generally controlled in the PPharmmacoutical-synthesis by conducting regulatory impurity testing. Ths typically entails residual solvents (hat are not used in further downstream processing) or process impurities (in cases where they conclusively demonstrate that these moieties are not also degradation products). I is important to remember that this step is the last major source of potential impurities, therefore, itis very desirable thatthe methods used for analysis this stage be rigorous. It should be remembered that base-1- salt or acidto-salt conversions could also generate new impurities. Furthermore, thermally labile compounds can undergo decomposition if any further processing involves beating, 4.2, Formulation-relaed impurities ‘A number of impurities in a drug product can arise out of interactions with excipients used to formulate a drug product. Furthermore, in the grocess.of formulation, a drug substance is subjected 10a_variety, of conditions that” éan_Jead_to_its degradation or oihex deleterigus reactions. For example, iGbeat, gr used for @rying or for other reasons, it can facilitate tion of thermally labile drug substances Solutions and suspeusians.are potentially prone to degrada- tion that is.due to pydrolysi.or solvolysis (see kinetic studies discussed below). These reactions can also occur in the dosage form in qBolid stake, such asin the case of oxpsutes and tablets, Not only can the water used in the formulation contribute its ‘own impurities, it can also provide a ripe situation for hydrolysis and metal catalysis. Sipular-reactigns are_possible in other solvents that may be used. aie Hridation.so.possible Sor casily.oxidwzed materials if no precauuons.ore taken. “Similarly, dighksensitye, materials ‘can undergo photochemical reactions. Details are provided in Chapter 6 of reference Ti] regarding how various ex- cipients can contribute to degradation and the resulting impunties ery Reviews $9 2007) 31 4.3. Degradation-related impurities yurities can be produced fa the formulation matrix, eevelerated. silty cae “ar ans fe erous eager coins of - lity studies under various ¢ Dae end htc help ws ermine wha (for details see Chapter 8 of reference Up. itis ino n Ce ty as me studies_in_ monitoring and evaluating amnpurities 15 discuss: = -because-of APL was very ‘A umber of impt and evaluate 4.3.1. Kinetic studies ‘Most ofthe degradation reactions of pharmaceuticals occur acfinite rates and are chemical in-nanuge. These reactions are iecied by conditions such a5. solvent, concentration of feactunis, temperature, pH of the medium, radiation energy, fand the presence of catalysts. The order of the reaction is eserbed by the manner in which the reaction rate depends on the concentration of reactant. The degradation of most ‘pharmaceuticals can be classified as.z2r0 order, first order, or paeudo-fist ordereven though they play degrade. by. compli- ‘ics, mechanisinseand. the true. expression may be of higher ‘order or be complex-and noninteger. ‘An understanding of the limitations of experimentally bleined heat of activation values ic_cutical in stability, predictions, For example, the apparemt heat of activation of a PH value wherestwo or more mechansins of degradanon are ‘rvolved! isnot necessanly constant with temperature. iso, the ion product of water, pKw, is temperatute-dependent, and —-AHa ‘sepproximately 12 kcal, frequently overlooked factor that must be considered when calculating hydroxide concentration. There. fore, itis nesessary to obtain the heat of activation for all bimolecular rate constants involved in aiate-pH profile to predict legradation rates at all PH values for various temperatures It is incumbent upon the chemist to studies to predict stabili 5 Ahuja /Aanced Drug Delivery Reviews $9 2007) 3-11 drwy development [7]. Ensuring the safety of @ new pharma- eutical compound or drag requies that it meet the established purty standards a8-4 chemical entity or when admixed with Tnimat feeds for toxicity studies or pharmaceutical excipients for ‘bumaa use. Furthermore, it should exhibit excellent stability throughout its shelf life. These requirements demand that the analytical methodology tht is used be sensitive enough to mea- ‘ure tow levels of impurities. This has led to analytical methods that are suitable for determination of racelultratrace levels, ie, sub-mierogram quantities of various chemical entities [8.12]. ‘Avarety of methods are available for monitoring impurities “The primary criterion is the ability to differentiate between the compounds of interest. This rquirement reduces the availabil- ity of methods primarily to spectroscopic. and. separation petbeds ora combination thereof. ; 5.1. Spectroscopic methods The following spectroscopic methods can be used: * Ultraviolet (UV) * Infrared (TR) ‘+ Nuclear magnetic resonance (NMR) f Mass spectromenry (MS) UV at a single wavetength provides minimal seleotivity of ‘apalysia; however, with the availability of diode array detectors (DAD), it is now possible to get sufficient simultancous information at various wavelengths to ensure greater selectivity 5.1.1. Infrared spectropivotometry Infrared spectrophotometry provides specific information on ‘some: functional .groupsetbat may allow quantification and selectivity. However, dowslevel. detectability is frequently a problem that may require more involved approaches to circumvent the problem. 5.1.2. Nuclear-magnetic resonance spectroscope Nuclear magnetic resonance spectroscopy provides fairly ‘structural nfoxmmasios on a molecule and is a very useful method for characterization of impurities; however, it has rosie. use as:a-quaptitatve method because of cost and time ‘considerations. 5.1.3. Mass spectrometry ‘Mass: spectrometry. provides -excollent.structural informa- tion, and, based on tht resolution of the instrument, st may provide an‘ieffeotive tool fortitfereatiating .molecules, with small differences in molecular weight. However, @-has lumuted Ute -asaanquantitative-teohnigue. because of Bost~and time considerations. In summary, eNiaRvend MS.ace.excellentsechniques for ‘choructecizatign of smpusitics shat have-been isolated by any of the techniques discussed above. UM-tas been found to be especially useful for analyzing most samples with high-pressure liquid chromatography. his combination is commonly used in pharmaceutical analysiay 5.2, Separation methods can be used “The following separation methods ¢3% + Thin-layer eromatography «mcy + Gas chromatography (GC) 1 fle prsoure liquid chromatography (HPLC? + Capillary electrophoresis (CF) + Supercritical fluid chromatography ofthe above-listed methods 18 BV their potential use (10} Te techniques are chromatographic horetic method that 15 frequently thods because it shares (SFO) Jen here 10 A brief account provide a quick review of Except for CE, all thest methods, CE is an electrop! a wh he eaowarhie Me aioe the common requirements ‘of chromatography. vvaver, itis not stcly a two-phase Separation system rower jroment in ehvomatography. Hyphenated methods Pach ag GC_MS, LC-MS, GC-LC-MS, LC-MS-MS, ete. are all discussed later in this chapter. : ‘A broad range of compounds can be resolved using TLC By utilizing a variety of different plates and mobile phases. The primary difficulties related to this method axe limited resolution, detection; and-ease-of quantification, The greatest advantages are the case of use and low cost. Gas chromatography is a very useful technique for quanti- fication. Itcan provide the desired resolution, selectivity, and cease of quantification, However, the primary limitation is that the sample must be Volatile or bas to be made volatile by derivatization, Ths technique is very useful for organic volatile impurities, ‘High-pressure liquid chromatography is frequently casually referred to as high-performance liquid chromatography today. Both of these terms can be abbreviated as HPLC, and they are used interchangeably by chromatographers. This is @ useful technique with applications thet have been. significandly _gstended forthe pharmaceutical chemist by the use of a variety of detectors such as fluorescence, electromeirie, MS, etc. ie Capillary. clecophoresis is a useful technique when very low ies of snp ae avalble and hgh reson jired. The primary difficul the injected samples. S488 Feproducibiliy, of “Superentical fluid. chrom: atogr advantages of GC i terms of detestion sod TPL a separation, ith olay af the sor ee, tes of imporance.Fhs technique is sil eveiving eng eet ‘application has been found evolving, and its greatest ‘im the extraction of samples. —~ 5.3. Hyphenated methods The following hyphenated reth fe-moniior impuniies 3]. NMS CAM Be Used effectively sai S Aha Advanced Drag Delery Rees $9 (2007) 3-11 + LC-DAD_NMR-MS SLC MS-MS. (Of course, these methods are not always avaiable or applicable —~ a detailed discussion is included in Chapters 4 4nd 9 of reference [1] as #0 why itis not always possible to use these methods. In ca8e it 8 nocessary 10 procure authentic rmatenal for purposes of structure confirmation, synthesis or tsolation methods should be utilized 6. impurity profiling Ideally an impurity profile should show all impurities in a single format wallow monitoring of any variation ia the profile because of planned or unplanned changes in synthesis, fommultion, or stability, ete. The diving forces for studying an impunty profile are Jusity considerations * {egulatory (FDA) requirements I is the belief of this author that quality considerations should be the driving force for profiling. 6.1, Samples to be profiled Impurity profiling should be done forthe following samples: Active ingredient Process check (synthesis or formulation) Final product. 6.2. Components seen in a profile ‘Ideally, an impurity profile should show the following: + Synthesis related impurities FFonnutation-related impurities + Degradation products * fnteraction products, 7. Isolating impurities It is offen necessary to isolate impurities because the instrumental methods mentioned above are not available or further confinnation is needed. For example, when hyphenated ‘methods such as LC-MS are not suitable or do not provide lunambiguous charactenzation, it may be necessary w.ssolate ‘mpurives-for-further-gonfirmation of structure or for conduct- \ag-soncity: stdigs. OF couse, after the structure has been cstablished, these impurities can be synthesized by a suitable route, The following methods have been used for isolation of impunties: Solid-phase extraction Liquid. nquid extraction + Accleted solvent extraction + Sopereneal Thad extacton “{Ceterm dromaopenty 3 fash eromatogaphy 7 thiriyerchromatnrophy Ga chromate | igs pesure ignd chromatography + Capity elcrophorei 4 Saperctiea ad ehromstograpy. ttn ua a ct ln 8. Characterization of impurities ‘The characterization of impurities is generally achieved by the following means: + Matching retention data uv aR = NMR Ss: Once an impurity has been detected, it becomes necessary to estimate its content. Detectablity frequently means that a given ‘component provides a signal at least twice that of background noise or the baseline. For quantification of impunty, the mul "TIME tminuess? Fig 1 Reston of pti phone, 2-3.5tihydonybensae a, Prosues. 1 = bydroisoquinoline, pa S-dihydronyaccto Fi 3-2 xbutyge, actuate, $=3.5-dinydrony gee MONON teu ——_______ "TIM iat” Fig. 2 Revolution 0 potent diberyloxypheny impuctie. 1~leuatin, 2rsohvent, I-sclen, 4=0{(ebuylaminolehyiSsaienapheghene Kobo, $armhy 3 Saberelonybene! skola, fos sdheoe, tephenone, 7~:lbenshebiyamino meth lk3.-tbenslongere hol, F=15 divamlory-2.-

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