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COMMENTARY Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Acetaminophen (Paracetamol

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School of Pharmacy, National & Kapodistrian University of Athens, Athens, Greece JW Goethe University of Frankfurt, Frankfurt, Germany College of Pharmacy, University of Michigan, Ann Arbor, Michigan

Leiden/Amsterdam Center for Drug Research, Leiden University, Division of Pharmaceutical Technology, Leiden, The Netherlands University of Saskatchewan, Saskatoon, Saskatchewan, Canada Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland Pharmaceuticals Division, College of Pharmacy, University of Texas at Austin, Austin, Texas RIVM, National Institute for Public Health and the Environment, Bilthoven, The Netherlands

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Received 15 April 2005; revised 15 June 2005; accepted 13 August 2005 Published online in Wiley InterScience ( DOI 10.1002/jps.20477 ABSTRACT: Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product. ß 2005 Wiley-Liss, Inc. and the American
Pharmacists Association J Pharm Sci 95:4–14, 2006

Keywords: absorption; Biopharmaceutics Classification System (BCS); acetaminophen; paracetamol; permeability; solubility
Correspondence to: Dirk M. Barends (Telephone: þ31 30 2744209; Fax: þ31 30 2744462; E-mail:
Journal of Pharmaceutical Sciences, Vol. 95, 4–14 (2006) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association



20 0. with respect to its biopharmaceutical properties and the risk of waiving in vivo bioequivalence (BE) testing for the approval of new and/or reformulated immediate release (IR) solid oral dosage forms. Its structure is shown in Figure 1. MAs have been also given to granulates. Claremont. the thermodynamically most stable modification. NO.1 Briefly.BIOWAIVER MONOGRAPH FOR ACETAMINOPHEN 5 INTRODUCTION A monograph based on literature data is presented on acetaminophen. Therapeutic Indication and Therapeutic Index Acetaminophen has analgesic and antipyretic properties and weak anti-inflammatory activity and is used in the symptomatic management of Figure 1.17 Partition Coefficient A logP (n-octanol/water) value of 0.31(log P). However. Structure of acetaminophen. metabolism. excretion..25–27 JOURNAL OF PHARMACEUTICAL SCIENCES. 1. stereospecificity.21 and 0.5 at 258C is reported.2 propranolol. The purpose and scope of these monographs has been discussed previously. notably lacking the gastrointestinal (GI) side effects of aspirin and ibuprofen. JANUARY 2006 EXPERIMENTAL Published information was obtained from PubMed. is relatively common and can be extremely serious.4.4.1 chloroquine.4.16.23 The optimum single dose for adults is 1 g.2 has been measured. whether accidental or deliberate. VOL.0.7 mg/mL at 208C. solubility.15 Other sources report an aqueous solubility of 14.6 CHEMICAL PROPERTIES Polymorphism Three metastable forms of acetaminophen are known. CA) gave values of 0. also widely known as paracetamol. distribution.25–27 effervescent tablets.3 mg/mL at 258C. No other selection criteria were used.1 moderate pain and fever. indication. polymorphism.18 and 23. Ingestion of 10–15 g of acetaminophen by adults may cause severe hepatocellular necrosis and doses of 20–25 g are potentially fatal.7–12 Orthorhombic acetaminophen is suitable for direct compression tableting and may also be slightly more soluble13 but has been crystallized only in small quantities and the only commercially available form is monoclinic acetaminophen.22 Dose and Dosage Forms Strengths The WHO recommended dose is 100–500 mg. and dissolution. acetaminophen.24 Acetaminophen drug products with a marketing authorization (MA) are conventional IR tablets and capsules.4.17 14. the aim of the present study is to evaluate all pertinent data available from literature sources to assess the appropriateness of such a biowaiver from the biopharmaceutical point of view and also from the perspective of public health. Its chemical name is N-(4-hydroxyphenyl) acetamide. 95. Key words used were: paracetamol.14 Solubility One part of acetaminophen is soluble in 70 parts of water at room temperature15.3 and verapamil. Biobyte Corp. GENERAL CHARACTERISTICS Acetaminophen has INN name: paracetamol. absorption. up to 08/2004 and through the International Pharmaceutical Abstracts.1 ranititine. . Monographs have been published on atenolol.89(log P).5 However.19 Calculations using fragmentation methods based on atomic contributions to lipophilicity and by using the ClogP program (version 3.4 When taken at recommended doses it has an excellent safety profile.16 and soluble 1 in 20 parts in boiling water. dose. acute overdosage with acetaminophen.49(ClogP).7 mg/mL at 378C. partition coefficient. permeability.21 pKa An acidic pKa of 9.

.31 but other authors reported AUC values and peak plasma concentrations to be dose-dependent at doses between 325 and 2000 mg. From acetaminophen’s diffusivity value (6. where D is the solute aqueous a In most situations Paq* (the dimensionless aqueous permeability49) is not rate limiting.53.4.58 Binding to red blood cells is reported to be 10%–20%.2 cm for the radius of rat intestine. this monograph pertains to conventional IR solid oral dosage forms containing acetaminophen as the sole API.24. the wall permeability and the effective wall permeability in the rat can be calculated for the corresponding dimensionless numbers to be 0.62 –64 The clearance ranges between 11.61 Total urinary recovery of acetaminophen in 24 h is reported to be 71.2 whereas using the chronically isolated rat jejunal loop model they estimated À the Á dimensionless effective wall permeability PÃ eff of 0.9 and 4.25–28 Drug products containing acetaminophen in combination with other active pharmaceutical ingredients (APIs) can have a MA.8 and 22.47 using a single-pass intestinal rat perfusion technique. as free and/or conjugated. no significant differences in Cmax and AUC0 ! 1 were found between rapidly disintegrating tablets and conventional tablets. using the Ussing chamber. In rabbits. and syrups.31–34 Peak plasma concentrations are reached within 0. 95.09 Â 10À4 cm/s.62. NO.62 PHARMACOKINETIC PROPERTIES Absorption and Bioavailability The absolute bioavailability (BA) in the fasted state was reported in the range 62%–89%.9 Æ 0. Most studies were carried out in humans.3 h.43 Food reduces the absorption of acetaminophen tablets by increasing tmax and decreasing Cmax values. Lu et al.29–32 The incomplete absolute BA is caused by a presystemic clearance of about 20% of an oral dose.46 Although there are no direct published data on the absolute BA in the fed state. for acetaminophen to be 0.44.17–1.4.34 and but two animal studies have been also reported.86 Â 10À4 cm2/ min)47 and assuming 0. by using the relationa ship Pw ¼ P* w(D/R) .22. 20%–50% of the drug may be bound to proteins. Such formulations contain 500 mg per tablet.29.48 estimated the dimensionless wall permeability.51 Distribution The apparent volume of distribution of acetaminophen is reported to be 0.5%–95%.67 In JOURNAL OF PHARMACEUTICAL SCIENCES.32.25–28 diffusivity and R is the radius of the intestine.22. VOL.3 L/h32. i. Using rat perfusions. PÃ w .53.35 –43 The oral absolute BA was reported not to vary with the dose in range between 5 and 20 mg/kg.59 Of the acetaminophen present in breast milk.36.31 The elimination half life is reported to be between 1.57 After overdosage.35. Thus.35.41.86 Æ 0.25–28 However.45 Food effect is primarily due to delays in gastric emptying. DOSAGE FORM PERFORMANCE Excipients and/or Manufacturing Variations The relative BA of acetaminophen from solid dosage forms has been studied frequently. the permeability of acetaminophen through the rat jejunal wall was measured to be 0.56.52–56 Plasma protein binding is 20%–25% at usual therapeutic concentrations.6 Æ 0. the Ussing chamber technique leads to Pw values that are often lower than the values estimated from intestinal perfusions.66 and the total plasma clearance of acetaminophen has been reported to show a 12% difference after 20 and 5 mg/kg doses.5 Â 10À4 cm/s and they estimated the fraction absorbed to be 80%. JANUARY 2006 .60 Metabolism and Excretion Acetaminophen is metabolized by microsomal enzymes in the liver.49 Recently. 1.56.54. 85% is bound to milk proteins.36 L/kg. of acetaminophen 0. the controlling *.54 Â 10À4 cm/s.56 Acetaminophen crosses the placenta and is present in breast milk56 with an average milk/plasma concentration ratio of about 1. Pw.e. food does not affect the total amount of acetaminophen reaching the blood. with 85%–90% of the drug undergoing glucuronidation and sulfation to inactive metabolites that are eliminated in the urine. A smaller amount is conjugated with cysteine and mercapturic acid and only 5% of the drug is eliminated unchanged in the urine. However. the equation could also be written as resistance is Pw Peff ¼ Peff*(D/R).50 This value is much lower than the values estimated from intestinal perfusion.44.6 KALANTZI ET AL.2 h postdosing.45 Permeability Stewart et al.69–1. measured the wall permeability.

BAs of the brands relative to the solution were 98%. for the rate of absorption. these MAs not necessarily indicate that in vivo JOURNAL OF PHARMACEUTICAL SCIENCES. reflecting differences in rate of absorption. Retaco et al. 95% and 99%. The differences in gastric emptying were thought to be more pronounced in the fasted state and the differences in disintegration more pronounced in the fed state. NO. for acetaminophen. The results demonstrated that addition of 630 mg sodium bicarbonate increased the rate of absorption of acetaminophen relative to both the conventional tablets and the soluble tablets. these differences were not statistically significant and only the amount excreted from 0 to 4 h varied with the formulation.76 Of special interest are recently introduced acetaminophen products containing large amounts of sodium bicarbonate. as indicated by AUC. as indicated by tmax. Walter-Sack et al. was comparable among the three brands. and found that the extent of absorption. differences were found during the early stages of the absorption process.77 who compared an acetaminophen tablet containing 630 mg sodium bicarbonate with a conventional tablet. However. respectively. The rate of absorption. Sotiropoulus et al. In one of the earliest relevant studies. no significant differences were found between two conventional tablets. was about twice as fast compared to the conventional tablets. were observed. being the innovator. differences in rate of absorption between drug products were sometimes found. but the other tablet. one containing 400 mg sodium bicarbonate and the other containing 630 mg sodium bicarbonate. this cannot be assumed. whereas the addition of 400 mg sodium bicarbonate increased the absorption rate of acetaminophen relative to conventional acetaminophen tablets only.81 The NL list is still valid for national applications. However. but the MA granted under that provision remained in place. did not exhibit differences between formulations. 1. indicated by t50% and t90%.BIOWAIVER MONOGRAPH FOR ACETAMINOPHEN 7 dogs. expressed as AUC0 ! 1.37 compared the pharmacokinetics of one commercially available acetaminophen tablet and one soluble commercially available acetaminophen tablet with two development tablet formulations. reporting a BA relative to the liquid dosage form of 82%. MAs of solid oral dosage forms were taken as indicators that these drug products had successfully passed an in vivo BE test.74 using urinary excretion data. expressed as Cmax and partial AUC values. Sevilla-Tirado et al. respectively.70 evaluated the BA of three brands of acetaminophen tablets in comparison to a solution.68 Studies in humans in general show similar results. It was suggested that a combination of faster disintegration and gastric emptying of the tablets containing sodium bicarbonate is responsible for the faster rate of absorption. These findings were recently confirmed by Kelly et al.76 compared three tablets.76.78 The excipients used in IR solid oral dosage forms having a MA in Germany (DE).72 did not display statistically significant differences in BA. one effervescent tablet. both in the fasted state and the fed state.71 compared a solid and a liquid oral dosage forms that did not show differences in the AUC0–12 h and in Cmax.77 The data of Grattan et al. acetaminophen is on such a list. 95. Greece (GR). the amount excreted during the first hour varied among the formulations. Hekimoglu et al.69 evaluated three tablets and one liquid acetaminophen product for their comparative BA. and Kelly et al. but differences in the urinary excretion during the first hours. Such dosage forms are claimed to have fast drug absorption. In previous monographs. with differences being not statistically significant. JANUARY 2006 .1 However. was significantly shorter than those of the innovator. While the absorption rate of one brand. Bababola et al. An evaluation of four brands of acetaminophen tablets by Hekimoglu et al.79 Also in NL. the extent of absorption.80 The DE list was recently withdrawn. VOL. had a somewhat slower absorption rate. and 92%. differences were observed. Dominguez et al. are supported by earlier reports that effervescent tablets show faster absorption characteristics than conventional solid tablets. two tablets had a rate of absorption as fast as the effervescent tablet.73 studied the BA of two lots of paracetamol tablets and although the total amount excreted in urine was similar between the two formulations. So. However.75 reported a study of two commercial brands versus the innovator. 87%. Grattan et al. The ‘‘bioavailability committee’’ of the regulatory authorities of DE classified acetaminophen in 1998 as an API for which in vivo BE testing was not required. and a powder sachet. as indicated by a shorter tmax and higher Cmax. Finland (FI).80 It is also possible that FI and GR have granted MAs without requiring in vivo GR studies. reported nonsignificant differences in the rates and relative BA’s ranging from 94% to 131% of three commercial formulations versus the innovator. based on urinary excretion data. and The Netherlands (NL) are shown in Table 1. While most studies report no difference in extent of absorption.

Captin1 Tabletten 500 mg. 40. 46). 35. omhulde tabletten. 1. GR (36). Paracetamol 500. GR (17. 21. 10. tabletten. 52. 44). 27) FI (1. Paraceon1 500 mg tabletit. FI (1. FI (14). and The Netherlands (NL) Carnauba wax Cellulose Croscarmellose Croscarmellose sodium Crospovidone Ethyl parahydroxybenzoate Gelatin Glyceryl palmitostearate Hydroxypropylcellulose Hypromellose Lactose Macrogol Magnesium stearate Maize starch Maize starch. Benuron1 Tabletten. 25–27. Panadol Gladde Tablet. 42. Mono Praecimed1 Tabletten. 22. 14. 53). 40. 16. Finland (FI). tabletten. omhulde tabletten 500 mg. NL (2. 21) DE (3. 33) NL (23) DE (4–8. 43. 5. 38. 45). tabletten. Paracetamol 500 mg. 41) FI (37). NL (2) DE (42). Paracetamol CF 500 mg. Panadol 1000 mg Artrose. tabletten. Para-Tabs 500 mg tabletti. 95. NL (2. FI (15). oral suspension. 40. 37–39. 44. NL (33. 36). 25. 4. 11). 9. Apotel UniPharma filmcoated tablets 500 mg. 18. and powders for oral solution.38. 48. ¨a ¨ llysteinen tabletti. Paracetamol Tabletten Lichtenstein. 21. 46. 15. 38. Table 1. 15. GR (28. NL (29–31) NL (24) DE (35). 9. FI (14. 46). 11. 29. 38. c Excluded are dosage forms that are swallowed by the patient in liquid form: effervescent tablets. 37). 26. 19. Paracetamol Sandoz1 500 mg Tabletten. NL (19. 23. Panadol Forte 1g tabletti. Paracetamol 500 mg. 53). FI (16. tabletten (MA holder: Delphi Pharmaceuticals). 47–52) DE (12. 42. Paracetamol kalvopa STADA1 500 mg Tabletten.36). 11. 20) FI (1. GR (17). 37. 53. 16. 43). NL (2. 11–13. 23. 47) NL (33) FI (1). NL (21. 48–52) NL (33) FI (37) DE (3–11. 8. 20–22. FI (1 . GR (17. FI (1. Excipientsa Present in Acetaminophenb IR Solid Oral Drug Productsc with a Marketing Authorization (MA) in Germany (DE). tabletten. tabletten 500 mg (MA number: 50954. 46). 6. 34. Squibb tab 500 mg. b Drug products containing other drug substances than acetaminophen are excluded. Paracetamol Alpharma 500 mg. GR (43). GR (28. 39). tabletten 500 mg (MA holder: Imgroma). GR (28). 24. 35.8 KALANTZI ET AL. 9. 29–31. 45. 33. Paedialgon1 Tabletten. 39). FI (14. soluble Stearic acid Stearic palmitic acid Talc Triacetin FI (1). Ben-u-ron1 Kapseln. 41) ¨a ¨ llysteinen. 41. oral powders and granulates. 40. FI (1. 18–27) NL (21) DE (4. NL (24. Paracetamol 500 mg. 15. 40. 14–16. 40. NL (2. 33) DE (4. 36. 33. NL (2) NL (29) DE (5. oral solution. tabletten 500 mg. 15. Paracetamol 500–1 A Pharma Tabletten. 39. 34). Depon Bristol. 39). pregelatinised Methyl parahydroxybenzoate Polydextrose Potassium sorbate Potato starch Potato starch. 1. 13. 37–39. 41) NL (40) DE (5–7. NL (2) DE (3–13). tabletten 500 mg. 41. NL (18–20. Paracetamol Sandoz 500. 43). 48–52) NL (18. capsules 500 mg. 27. 47. 32. 15. 39. NL (2. 34. 44. tabletten. 20. 42). 8. colorants and flavors are not included. Pijnstillende en koortsverlagende paracetamol tabletten 160 mg/250 mg Samenwerkende Apothekers. Paracetamol 500 von ct Tabletten. Paracetamol beta1 500 Tabletten. 50. NL (27) NL (33) DE (3. tabletten 500 mg (MA holder: H. 32). 22. NO. NL (29–31) DE (3. Kinderparacetamol CF 100 mg. tabletten. 27) NL (24) FI (1). Panadol 500 mg tabletti. Paracetamol FLX 500 mg. PAMOL1 500 mg. 24. Chewable tablets are also excluded. Paracetamol 500 HEXAL1 bei Fieber und Schmerzen Tabletten. 10. Paracetamol 500 PCH. 31. 40. Paracetamol 500 PCH. Democyl 500. 13. 32. 32) DE (3. 46). 49. 36). 44. Fensum1 500 Tabletten. filmomhulde tabletten 500 mg. kalvopa ¨a ¨ llysteinen. 36. Paracetamol CF 500 mg. NL (2. Ten Herkel). 4. 11. 23. 27. Enelfa1 Tabletten. Paracetamol 500 mg ‘Therapeuticon’. Panadol Sterling tab 500 mg. 44. 10. 25. Paracetamol. Momentum. 30. 13. 41) NL (22) FI (1). tabletten. Apotel Uni-Pharma tab 500 mg. pregelatinised Starch. GR (36. Sinpro1 N Tabletten. kalvopa ¨a ¨ llysteinen. 3. JOURNAL OF PHARMACEUTICAL SCIENCES. dispersible tablets. Paracetamol BC 500 mg Tabletten. 53). orodispersible tablets. GR (36). Paracetamol-ratiopharm1 500 Tabletten 12. 37–39). tabletten. 22. 45. GR (17). 18. a Printing ink. 40. NL (26. 6–8. tabletten (MA holder: HEALTHYPHARM). 45. 46). 41. NL (2. NL (18–20. 38. 24–26. 21. 2. 16. 19. tabletten (MA holder: KATWIJK FARMA). GR (17). 33. 17. 14–16). 47–52) DE (32). FI (14.44. 10. Paracetamol 500 mg. JANUARY 2006 . 38. 45). 41) FI (1. 39. 33. Pijnstillende en koortsverlagende paracetamol-tabletten 500 mg Samenwerkende Apothekers. tabletten 500 mg (MA number: 50480). tabletten (MA holder: GENRX). PARAMAX Rap 500 mg tabletti. 29–31. VOL. 43). Greece (GR). 42. Panadol Zapp. 51. Paracetamol 500 mg Katwijk. 28. 41. NL (2. modified Povidone Propyl parahydroxybenzoate Propylene glycol Silica Sodium cyclamate Sodium hydrogen carbonate Sodium lauryl sulfate Sodium starch glycolate Sodium stearate Starch. FI (1. 21–23. 46). kalvopa 4. 7. Panadol Zapp 500 mg tabletti. NL (2. Paracetamol AL 500 Tabletten. 8. 16. GR (28. Paracetamol-ratiopharm 500 mg tabletti. 6–11. 44.

The T50% values for in vitro dissolution were 50 min for a generic tablet and 1 min for Tylenol1 and Datril1.e. established a level A correlation between the percentage dissolved in vitro and percentage absorbed in vivo. therefore. 1.85 The same is true in media simulating the fed state conditions in the small intestine. The authors explained this correlation from the low stirring speed.84.87 Permeability To date.77 Although delayed in vivo dissolution has been observed in the fed state71.68. respectively. but at a stirring speed of 30 rpm instead of 50 rpm.82 To the best of our knowledge there are only three reports that claim some kind of correlation of in vitro dissolution data with in vivo data. did show differences in in vitro dissolution although their BA’s relative to a solution were close to 100% for all brands.8.84 Although in the fed stomach77 or under conditions that simulate the fed intragastric conditions68. showing faster absorption than conventional solid dosage forms.68.1 N HCL. from three brands of acetaminophen tablets. NO.83 using the USP dissolution method with medium pH 5. data in humans77 and in dogs68 suggest that at least the products that are currently in the European market are unlikely to show dissolution dependent rate in absorption in the fed state because the gastric emptying limits the absorption kinetics. the cut-off limit for an API to be ‘‘highly soluble’’ as defined by the present BCS Guidances. as can be derived from the MA’s granted to acetaminophen syrups and effervescent tablets. Dominguez et al.8. a series of studies show that different acetaminophen formulations meeting USP dissolution criteria were all bioequivalent. Moreover. Dissolution and In Vitro – In Vivo Correlation The USP 26 specification for acetaminophen tablets is not less than 80% (Q) of the labeled amount dissolved in 30 min in 900 mL pH 5. the dose to solubility ratio is 21 mL.74 established a weak correlation between mean dissolution time and mean residence time. 95. at 50 rpm. 500 mg. Differences in rate of absorption between the different acetaminophen drug products are tolerated by regulatory authorities. in which in vivo BE was observed despite differences in in vitro dissolution.. Although internal standards were not used. Tylenol1 and Datril1.37.7 mg/mL at 378C for the solubility. In vitro dissolution data in Dominguez et al.. VOL. and 92%.44. by which the in vitro dissolution kinetics under that condition was supposed to resemble the population gastric emptying kinetics in vivo.BIOWAIVER MONOGRAPH FOR ACETAMINOPHEN 9 BE studies among these drug products have been conducted.8 phosphate buffer using the paddle apparatus operated at 50 rpm.73 Similar results were observed in the study of Hekimoglu et al.72.75 has suggested that the systemic absorption of acetaminophen might not be dissolution rate limited and hence using in vitro dissolution rate studies alone to establish BE of acetaminophen tablets should be done with caution. This value is less than 250 mL. its solubility does not vary with the pH.71 products that are currently in the European market are unlikely to show dissolution dependent BA.69 found that the rate and amount of acetaminophen excreted may be related to the in vitro dissolution rate in 0. For the highest strength.83 In vivo dissolution of IR tablets in media simulating the contents of the GI lumen in the fasting state is usually rapid. using the rotating basket apparatus at 85 rpm. using the paddle apparatus. Rostami-Hodjegan et al. 87%.74 study were obtained in phosphate buffer pH 5. JANUARY 2006 . these data suggest that acetaminophen should be classified as low JOURNAL OF PHARMACEUTICAL SCIENCES.8 and in HCl 0. respectively.8 using the rotating paddle apparatus at 50 rpm. i. permeability data for acetaminophen have been collected with rat perfusions and/or using the Ussing chamber only. there are many reports showing no correlation between in vitro dissolution and in vivo data. for the generic tablet.1 N in the paddle apparatus operated at 50 rpm..75 This is supported by the study of Retaco et al.85 dissolution can be significantly retarded. whereas the relative BAs with respect to acetaminophen powder were 82%. carried out in phosphate buffer pH 5.77 DISCUSSION Solubility Acetaminophen is not substantially ionized at pH less than 9 and.77 and this has been reported to affect blood levels. where a comparison of the dissolution data obtained in phosphate buffer pH 5.68. Bababola et al.84.86. taken the value of 23. In contrast. Sotiropoulus et al. showing that the in vitro dissolution rates needed to be vastly different to predict differences in relative BAs.68.

data in rabbits suggest that high concentrations of osmotically active excipients such as mannitol may have an impact on the tmax of acetaminophen. will occur to the test product as much as to the reference product. i. Classifying acetaminophen as ‘‘low permeable’’ has also been suggested by others. i.74 However.e. extensions of the present requirements to BCS Class III APIs have received increasing attention. just below the critical value of 90% absorbed..86. literature suggests BE of acetaminophen products with respect to extent of JOURNAL OF PHARMACEUTICAL SCIENCES. the data are always collected on a crossover basis.’’ although on the borderline. detecting differences in in vitro dissolution between products that are actually in vivo bioequivalent. differences between the Cmax of the test product and the Cmax of the reference product. However. differences between brands and test formulations have been observed. as in the case of tablets containing high amounts of sodium bicarbonate.8 was inadequate to detect in vivo bioinequivalence. It was suggested that these differences were caused by differences in disintegration and/or gastric emptying rates. In in vivo BE studies. 95.86. Both of the current BCS Guidances allow the possibility for a biowaiver exclusively for BCS class I drugs.. Most experimental results confirm these expectations.87 The percent of dose absorbed can be estimated by adding the percent biotransformed during first-pass from the liver to the absolute BA.e. although possessing properties borderline to BCS Class I. cannot be ruled out. then by which method. absorption rate.21. 1. So it can be assumed that acetaminophen is not a narrow therapeutic index drug. Absorption rate differences. these effects of intestinal metabolism cancel each other out.21 as BCS Class IV is probably due to use of incorrect solubility data. to differences between the AUC of the test product and the AUC of the reference product. But there is some evidence that comparative in vitro Risks for Bioinequivalence Caused by Excipients and/or Manufacturing Parameters As discussed above. i. The cut-off limit for an API to be classified as ‘‘highly permeable’’ by the present BCS Guidances86. This suggests that the fraction of dose absorbed is higher than 80%.87 The permeability of acetaminophen.89 Intestinal metabolism.89 The classification of Kasim et al.87 The therapeutic indications of acetaminophen are not critical and there is a wide difference between the usual therapeutic dose and toxic doses. However. permeability compound because wall permeability is less than the generally considered borderline value of 2–4 Â 10À4 cm/s. Only one report claimed that the USP test at pH 5. absorption. Although data in humans are lacking.88 More important is the fraction dose absorbed in humans.e.87 is a fraction of dose absorbed to be higher than 90%. using the wider confidence intervals without showing the power of the statistical analysis. NO. are not known and can be further minimized if the test product is formulated with excipients used in those drug products already having an MA. VOL. CONCLUSION Surrogate Techniques for In Vivo Bioequivalence Testing Only in vitro dissolution has been used as a surrogate technique to detect in vivo bioinequivalence up to now. in vivo–in vitro correlations are not expected. so. These data lead to classifying acetaminophen as ‘‘low permeable. According to the present regulations. For an API that is on the borderline between BCS Class I and III. after administration.. Other workers also classified acetaminophen as BCS Class III. acetaminophen is a BCS class III API. which is the basis of the permeability classification in the present BCS Guidances. JANUARY 2006 .10 KALANTZI ET AL.67 Patient’s Risks Associated with Bioinequivalence When considering a biowaiver for a drug substance. its therapeutic use and therapeutic index also needs to be taken into account. Comparative in vitro dissolution testing will provide even greater assurance of BE with respect to at least the extent of absorption. although few workers have found limited correlations.86. The important question is whether in vitro dissolution is able to detect bioinequivalent products and if so. formally excludes it from the present biowaiver criteria. glucuronidation and/or sulfation. Also. in vitro dissolution can be expected to be over-discriminatory.90–93 Formulation effects giving rises to differences in the extent of absorption. as reported above. in this study bioinequivalence was declared on the basis of urinary excretion data.

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