Twenty years ago, dissolution media were used

Transcription

1 dx.doi.org/ /dt210314p6 Evolution of Dissolution Medi Over the Lst Twenty Yers Jennifer Dressmn Institute of Phrmceuticl Technology, Goethe University, Frnkfurt m Min, Germny e-mil: dressmn@em.uni-frnkfurt.de Twenty yers go, dissolution medi were used lmost exclusively for qulity control purposes in the phrmceuticl industry. The most common dissolution tests were for orl dosge forms, nd these were pproched ccording to the relese mechnism immedite relese (IR), enteric-coted (EC) tblets, nd controlled-relese (CR) tblets or pellets (beds). In the USP from 1990 (1), wter ws quite commonly used s dissolution medium. Alterntively, for poorly soluble drugs, solutions contining surfctnt, most commonly sodium luryl sulfte or polysorbte 80, were recommended to provide sink conditions. A third pproch of the dy ws to use medium tht could reflect conditions in the stomch or smll intestine. The medium for the stomch, Simulted Gstric Fluid Test Solution (SGF TS), ws both cidic nd contined pepsin, thus ddressing two of the fundmentl fetures of the composition of gstric fluids in the fsted stte. Likewise, the medium for the smll intestine, Simulted Intestinl Fluid Test Solution (SIF TS), ws slightly bsic (ph 7.5) nd contined pncretin to reflect the enzyme ctivity in this region. For IR products, typiclly just one of the bove medi ws recommended for dissolution testing. For exmple, theophylline IR products used wter s dissolution medium, metoprolol IR products used Simulted Gstric Fluid TS, nd probenecid IR products used Simulted Intestinl Fluid TS. If drug hd ph-dependent solubility, first line of pproch ws to use buffer in which the drug hd dequte solubility, s this mde it esier to estblish sink conditions. In some cses, the ph of SIF ws not high enough to provide sink conditions, nd for severl products more bsic buffer ws implemented (e.g., mephobrbitl, for which medium with ph of 10.0 ws used). If there ws no ph dependency in the solubility but the drug ws poorly soluble, n queous solution of surfctnt ws typiclly used (e.g., crbmzepine). In some cses where the drug hd ph-dependent solubility but sink conditions could not be chieved in one of the buffer solutions, surfctnt ws dded to the buffer with the best solubility (e.g., for spironolctone, the medium ws ph 1.2 plus sodium luryl sulfte, SLS). Another pproch for poorly soluble drugs ws to dd isopropyl lcohol to the medium, s in the cse of dydrogesterone, or n-propyl lcohol s in the cse of reserpine. Rrely, the volume of medium ws incresed to ttin sink conditions, such s in the cse of chloroxzone (1800 ml). These cse exmples underscore the emphsis on chieving sink conditions s first priority, rther thn try- 6 ing to reflect how the drug product would perform under ctul gstrointestinl (GI) conditions. A first step towrds evoking more physiologicl pproch ws the revision of the ph of simulted intestinl fluid from ph 7.5 to ph 6.8 (2), which cme into force with USP 25. This chnge ws mde to reflect the fct tht the ph in the smll intestine typiclly reches 7.5 towrd the end of the ileum, wheres the IR dosge form or EC dosge form is expected to relese the drug in the proximl smll intestine to enble sufficient contct time between the drug nd the intestinl mucos for bsorption. By the time the USP Generl Chpter <1092> Dissolution Procedure: Development nd Vlidtion ws introduced (3), it ws recognized tht physicl nd chemicl dt for the drug nd dosge unit need to be determined before selecting the dissolution medium. Among other informtion, the solubility nd solution stte stbility of the drug s function of ph s well s, for less soluble drugs, the influence of surfctnts on the solubility of the drug should be evluted. For the dosge unit, the key fctors re the intended relese mechnism, the dosge rnge (if severl strengths re to be produced), nd ny excipients tht cn modify the solubility properties of the drug. While Chpter <1092> continued to recommend tht the dissolution medium be chosen to ensure tht sink conditions re met, it ws lso noted tht medium tht fils to provide sink conditions my be justifible if it is shown to be more discriminting. The chpter lso implied tht the medium ph should not go outside the physiologic ph rnge of Chpter <1092> lso discourged the use of n queous orgnic solvent mixture s dissolution medium, while remining open to such composition if n in vivo in vitro reltionship hd been demonstrted. Further, the pros nd cons of wter s dissolution medium were extensively discussed, recognizing tht while wter is not representtive of conditions in the GI trct (physiologicl rgument) nd hs no buffer cpcity (reproducibility rgument), it hd been used for mny drug products over long period of time. All in ll, with the introduction of this chpter in USP 30, we cn see shift wy from sink conditions t ny price to more considertion of wht might be physiologiclly resonble. Revisions to Chpter <1092> hve recently been published in drft form (4, 5) nd re under discussion s of this writing. With regrd to the medium in which the dissolution test is conducted, the chpter continues to emphsize tht good knowledge of the solubility nd

2 Tble 1. Composition of Vrious Gstric Biorelevnt Medi Component SGF sp FSSGF FeSSGF Sodium turocholte (mm) Lecithin (mm) Pepsin (mg/ml) Sodium chloride (mm) Hydrochloric cid (mm) Glcil cetic cid (mm) Sodium cette (mm) Milk/Buffer - - 1/1 Chrcteristic prmeter ph Osmollity (mosm/kg) Buffer cpcity (mmol/l/δph) Simulted gstric fluid without pepsin is included s compendil medium for comprison. stbility of the drug substnce in vrious medi is key to selecting n pproprite dissolution medium. Surfctnts my be dded to the medi to ssist in ttining sink conditions for poorly soluble drug substnces, in which cse the dosge form effects on dissolution cn be evluted lrgely independently of the drug substnce effects. However, the concentrtion of surfctnt must be justified by compring results obtined with medi prepred t higher nd lower concentrtions of surfctnt. As n lterntive to the common synthetic surfctnts, nturl surfctnts such s bile slts nd lecithin cn be used in the composition of medi, which enbles the dissolution method to more closely resemble conditions in the proximl humn gstrointestinl trct. In prllel to the evolution in expecttions for qulity control dissolution methods, the need to be ble to forecst the in vivo performnce of drug during drug development hs lso been incresingly recognized. For this purpose, it is prticulrly importnt for poorly soluble drugs tht the in vitro test mimic the conditions in vivo s closely s possible. To chieve this gol, biorelevnt gstrointestinl medi tht simulte the fsted nd fed sttes were first proposed in 1998 (6). These medi, lso discussed in the revisions to Chpter <1092> s indicted bove, hve been used to exmine the solubility nd dissolution chrcteristics of severl clsses of drugs (e.g., poorly soluble wek bses nd wek cids, lipophilic drugs) to ssist in predicting their in vivo bsorption behvior (7 9). Biorelevnt in vitro dissolution testing is useful for qulittive forecsts of formultion nd food effects on the dissolution nd vilbility of orlly dministered drugs s well s for understnding how the drug product will relese the drug in vivo. It hs been observed tht results in biorelevnt medi, when coupled with physiologiclly bsed phrmcokinetic models, cn provide more ccurte simultion of phrmcokinetic profiles thn results in the compendil simulted gstric nd intestinl fluids (10). Thus, the use of biorelevnt medi cn gretly ssist with the selection of drug product prototypes to optimize in vivo performnce nd to understnd which dosing conditions re most pproprite. Also, mny post-pprovl formultion chnges (including new generic formultions) could be screened for bioequivlence using biorelevnt dissolution testing prior to being entered into phrmcokinetic bioequivlence studies. As such, the biorelevnt testing pproch provides mens of reducing the risks ssocited with product chnges nd in designing generic versions of existing drug products. The formultions nd the instructions on how to prepre the biorelevnt medi originlly developed by Dressmn et l. cn be found in pper published in Dissolution Technologies in 2004 (11). Since then, severl updtes nd lterntive medi hve been proposed. The compositions of the most widely used biorelevnt medi, FSSGF, FSSIF, FSSIF-V2 nd FeSSIF-V2, re provided in Tbles 1 nd 2. Additionlly, medium to reflect conditions in the stomch fter mel intke, FeSSGF, hs been published (12, 13). As this medium contins het-treted milk s one of the ingredients, some concerns hve been rised bout possible vribility in composition of the medium ccording to the source of the milk, the seson, nd so forth. Additionlly, smple nlysis is mde difficult when working with this medium becuse of the need to seprte the dissolved drug from the milk proteins. For this reson, one hs to precipitte the proteins nd then use rther corse filters (2.7-µm pore size), which of course crries the risk tht some fine, undissolved drug might lso be present in the filtrte nd thus contribute to the totl concentrtion mesured. For these resons, efforts re underwy to estblish good lterntives to the milk-bsed medium tht re esier to work with from n nlyticl point of view (14). A question tht is often rised during the formultion development phse is whether it is necessry to use biorelevnt medi to ssist in comprison of prototype performnce nd to predict whether the drug formultion combintion will hve food effect. This question cn often be nswered in the frmework of the Biophrmceutics Clssifiction Scheme (BCS). According to this scheme, which ws first proposed by Amidon et l. in 1995 (15), ech nd every drug cn be clssified ccording to its solubility nd intestinl permebility chrcteristics. As such, it pplies exclusively to dosing drugs orlly. If the drug should ct systemiclly, both the permebility nd the solubility clssifictions re importnt to screening for the bility of the drug to be bsorbed, but if the drug should ct loclly in the gstrointestinl trct, the solubility my be the primry fctor in ssuring tht the drug meets its trget. For drugs tht re highly soluble ccording to the BCS, the use of simple queous buffers is recommended for screen- 7

3 Tble 2. Composition of the Biorelevnt Smll Intestinl Medi Component (mm) SIF sp FSSIF-V2 FSSIF FeSSIF-V2 FeSSIF Sodium turocholte Lecithin Glycerol monoolete Sodium olete Mleic cid Monobsic sodium phosphte Monobsic potssium phosphte Glcil cetic cid Sodium hydroxide Sodium chloride Chrcteristic prmeter ph Osmollity (mosm/kg) ± ± ± ± 10 Buffer cpcity (mmol/l/δph) - 10 ± 2 10 ± 2 25 ± 2 76 ± 2 Simulted intestinl fluid without pncretin is included s compendil medium for comprison. ing formultions. However, if the drug does not meet the criteri for highly soluble ccording to the BCS, it my be dvisble to use biorelevnt medi to screen for formultion performnce. Recently, supplementry scheme (16), the Development Clssifiction Scheme (DCS), hs been developed to help the formultor more precisely ssess drug chrcteristics within the frmework of formultion development. This scheme is set up to ssess whether drug dissolution is limited by prticle size or by solubility, nd thus gives the formultor vluble informtion not only bout whether drug bsorption will be limited by luminl events but lso on which formultion strtegies re most likely to succeed for the given drug to overcome these limittions. In ny cse, whenever the solubility or dissolution is limittion to drug bsorption, biorelevnt medi re useful to ssess formultion performnce nd food effects. This includes Clss II nd IV drugs of the BCS nd Clss II, IIb, nd IV drugs of the DCS, thus covering most drug cndidtes currently in the reserch nd development pipeline of mjor innovtor drug compnies s well mny of the drugs for which generic products re being developed. With such wide rnge of pplictions for biorelevnt medi, mny compnies re looking for wys of minimizing the costs nd mount of time required to prepre the medi. As one cn imgine, with such detiled composition, the biorelevnt medi tke time nd cre to prepre in reproducible mnner. To mke life esier for lbortory personnel nd t the sme time improve reproducibility of the medi, instnt versions of FSSIF nd FeSSIF hve been introduced to the mrket by Biorelevnt.com (www. biorelevnt.com). The so-clled SIF powder offered by this supplier is simply mixed with n lredy prepred 8 buffer nd wrmed to the experimentl temperture; it is then redy for the dissolution or relese test (17). One finl issue tht hs been discussed extensively in the lst yers is tht of the buffer choice for dissolution medi. Buffers re importnt to ensure tht the ph is mintined throughout the dissolution test nd hence to support reproducibility of the results. This is of course primrily considertion when the drug substnce or the excipients in the formultion hve ph-dependent solubility or disintegrtion chrcteristics. While Chpter <1092> focuses on dissolution for qulity control purposes nd suggests robust buffer systems like phosphtes or cettes, some uthors hve suggested tht since bicrbonte is the more prevlent buffer secreted in the intestines, it should be used for testing under intestinl conditions. The instbility of the ph of bicrbonte buffers due to interction with crbon dioxide from the tmosphere ppers to be the biggest block to its use in vitro (18). However, efforts re underwy to circumvent these issues for bicrbonte buffers (19). WHAT DOES THE FUTURE HOLD FOR DISSOLUTION MEDIA? As mentioned bove nd s reflected in the development of Chpter <1092> over the yers, dissolution testing hs been nd will continue to be prdigm in which the bility of the product to relese the drug under physiologiclly relevnt conditions is incresingly emphsized. Gone re the dys of extreme ph vlues in medi, huge medi volumes, nd orgnic solvent systems. This is becuse we incresingly recognize tht qulity in vitro should be linked to qulity in vivo; tht is, the drug product not only hs to relese the drug but lso relese it in

4 timely mnner consistent with the therpeutic ims of the drug product. This new prdigm for dissolution testing is completely consistent with the tenets of Qulity by Design nd ptient-centric drug development. As we increse our level of knowledge of the physiology t the site of ppliction, we will be ble to design more pproprite tests for drug products, including refinement of the existing biorelevnt medi. As suggested recently, set of medi tht tkes into ccount the vribility in humn gstrointestinl physiology might be prticulrly helpful in predicting vritions in dissolution nd hence bsorption, prticulrly for products contining poorly soluble drug substnces (19). Clerly, to better represent conditions under which extended-relese or pulstilerelese drug products relese the drug substnces, more knowledge will hve to be gined concerning the physiology in the lower gstrointestinl trct. Further, for some drug substnces, prticulrly those with good queous solubility (BCS Clss I nd III), nd for those drug products with robust relese ptterns under gstrointestinl conditions (e.g., osmotic pump-bsed relese), the use of simpler test designs is often wrrnted. So there is cler need to estblish some kind of decision tree to ssist formultors nd nlysts working with dissolution to select the right level of biorelevnce in the test design. In some cses, simple buffer medium my well be dequte, while in other cses more comprehensive simultion of gstrointestinl conditions will be pproprite. In these cses, we will look to instnt versions of the biorelevnt medi to ensure reproducibility, cut costs, nd reduce preprtion time in the lbortory. By coupling the results of dissolution testing with physiologiclly bsed phrmcokinetic modeling, we will be ble to trnslte dissolution test results into plsm profiles, which in turn cn led the wy to smrt selection of formultions nd the bility to recognize nd mitigte food effects erlier in the development process. With this pproch, we cn provide the link between the lbortory nd the ptient tht is crucil to the concept of Qulity by Design nd will ensure btch-to-btch nd product-toproduct therpeutic equivlence. This will boost confidence in qulity control dissolution testing on the prt of industril nd regultory scientists like. REFERENCES 1. The United Sttes Phrmcopei nd Ntionl Formulry USP 22 NF 17; The United Sttes Phrmcopeil Convention, Inc.: Rockville, MD, Gry, V.; Dressmn, J. B. Chnge of ph Requirements for Simulted Intestinl Fluid TS. Phrm. Forum 1996, 22 (1), Gry, V. A.; Brown, C. K.; Dressmn, J. B.; Leeson, L. J. A New Generl Informtion Chpter on Dissolution. Phrm. Forum 2002, 27 (6), Skwierczynski, R.; Curry, P.; Gry, V.; Krämer, J.; Stippler, E.; Suggett, J.; Mirz, T.; Brown, W. Revision of The Dissolution Procedure: Development nd Vlidtion <1092>. Phrm. Forum [Online] 2014, 40 (1). 5. Skwierczynski, R.; Curry, P.; Gry, V.; Krämer, J.; Stippler, E.; Suggett, J.; Mirz, T.; Brown, W. Revision of The Dissolution Procedure: Development nd Vlidtion <1092>. Dissolution Technol. 2014, 21 (1), Dressmn, J. B.; Amidon, G. L.; Repps, C.; Shh, V. P. Dissolution Testing s Prognostic Tool for Orl Drug Absorption: Immedite Relese Dosge Forms. Phrm. Res. 1998, 15 (1), DOI: /A: Nicolides, E.; Symillides, M.; Dressmn, J. B.; Repps, C. Biorelevnt Dissolution Testing to Predict the Plsm Profile of Lipophilic Drugs After Orl Administrtion. Phrm. Res. 2001, 18 (3), DOI: /A: Löbenberg, R.; Krämer, J.; Shh, V. P.; Amidon, G. L.; Dressmn, J. B. Dissolution Testing s Prognostic Tool for Orl Drug Absorption: Dissolution Behvior of Glibenclmide. Phrm. Res. 2000, 17 (4), DOI: /A: Kostewicz, E. S.; Bruns, U.; Becker, R.; Dressmn, J. B. Forecsting the Orl Absorption Behvior of Poorly Soluble Wek Bses Using Solubility nd Dissolution Studies in Biorelevnt Medi. Phrm. Res. 2002, 19 (3), DOI: /A: Otsuk, K.; Shono, Y.; Dressmn, J. Coupling biorelevnt dissolution methods with physiologiclly bsed phrmcokinetic modelling to forecst in-vivo performnce of solid orl dosge forms. J. Phrm. Phrmcol. 2013, 65 (7), DOI: /jphp Mrques, M. Dissolution Medi Simulting Fsted nd Fed Sttes. Dissolution Technol. 2004, 11 (2), Jntrtid, E.; Jnßen, N.; Repps, C.; Dressmn, J. Dissolution Medi Simulting Conditions in the Proximl Humn Gstrointestinl Trct: An Updte. Phrm. Res. 2008, 25 (7), DOI: / s Jntrtid, E.; Dressmn, J. Biorelevnt Dissolution Medi Simulting the Proximl Humn Gstrointestinl Trct: An Updte. Dissolution Technol. 2009, 16 (3), Kilic, M.; Arndt, M.; Jünemnn, D.; Dressmn, J. Fed Stte Simulted Gstric Emulsions Biorelevnt Dissolution Medi Bsed on the Gstric Snpshot Approch. AAPS Annul Meeting & Exposition, New Orlens, LA, Nov 15 17, Amidon, G. L.; Lennernäs, H.; Shh, V. P.; Crison, J. R. A Theoreticl Bsis for Biophrmceutic Drug Clssifiction: The Correltion of in Vitro Drug Product Dissolution nd in Vivo Biovilbility. Phrm. Res. 1995, 12 (3), DOI: /A: Butler, J. M.; Dressmn, J. B. The developbility clssifiction system: Appliction of biophrmceutics concepts to formultion development. J. Phrm. Sci. 2010, 99 (12), DOI: /jps

5 17. Boni, J. E.; Brickl, R. S.; Dressmn, J.; Pfefferle, M. L. Instnt FSSIF nd FeSSIF Biorelevnce Meets Prcticlity. Dissolution Technol. 2009, 16 (3), Boni, J. E.; Brickl, R. S.; Dressmn, J. Is bicrbonte buffer suitble s dissolution medium? J. Phrm. Phrmcol. 2007, 59 (10), DOI: /jpp Bergström, C. A.; Holm, R.; Jørgensen, S. A.; Andersson, S. B.; Artursson, P.; Beto, S.; Borde, A.; Box, K.; Brewster, M.; Dressmn, J.; Feng, K. I.; Hlbert, G.; Kostewicz, E.; McAllister, M.; Muenster, U.; Thinnes, J.; Tylor, R.; Mullertz, A. Erly phrmceuticl profiling to predict orl drug bsorption: Current sttus nd unmet needs. Eur. J. Phrm. Sci. 2013, 57 (16), DOI: /j.ejps