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664 Vol. 68, No. 7

© 2020 The Pharmaceutical Society of Japan

Chem. Pharm. Bull. 68, 664–670 (2020)

Regular Article

Utilization of Diluted Compendial Media as Dissolution Test Solutions with Low Buffer Capacity for the Investigation of Dissolution Rate of Highly Soluble Immediate Release Drug Products

Hiroyuki Yoshida,* Yasuhiro Abe, Naomi Tomita, and Ken-ichi IzutsuDivision of Drugs, National Institute of Health Sciences; 3–25–26 Tonomachi, Kawasaki-ku, Kawasaki 210–9501, Japan.Received March 16, 2020; accepted April 3, 2020

Research from the past decade has shown that the buffer capacities of intestinal fluids are much lower than those in the media used for dissolution test of many solid formulations. The purpose of this study was to elucidate the effect of buffer capacity on the dissolution profiles of highly soluble drug products, using meto-clopramide (a biopharmaceutics classification system [BCS] class III drug) tablets as a model. The dissolu-tion profiles of three metoclopramide products were obtained in Japanese pharmacopeia dissolution medium (pH 1.2 and 6.8), diluted medium with low buffer capacity comparable to that of gastrointestinal fluid, and other biorelevant media. One product showed slower dissolution in the medium with lower buffer capacity (bio-relevant, diluted compendial solution), but substantially similar dissolution in the compendial test solu-tions. Disintegration difference was implied to be involved in the different dissolution profiles depending on the medium buffer capacity. This study indicated the importance of media buffer capacity as a factor induc-ing different dissolution between products of highly soluble active pharmaceutical ingredients. The diluted compendial media would be a useful alternative to biorelevant media for the detection of the different formu-lation performances depending on the buffer capacities.

Key words  dissolution test; buffer capacity; highly soluble drug

IntroductionThe dissolution test is a valuable method for the character-

ization of the performance of oral solid formulations and other formulations. The dissolution test is utilized for two main pur-poses: the prediction of dissolution profiles of drug products in a gastrointestinal  tract; and for quality control  in specification tests. A predictive dissolution test is a potential tool to opti-mize product formulations and to understand the risk factors associated  with  changes  in  formulation  characteristics.1) It may also reduce  the requirements for a human bioequivalence study;  for  example,  through  a  biopharmaceutics  classification system (BCS)-based waiver. When the dissolution test is used as  a  quality  control  test,  it  is  expected  to  ensure  batch-to-batch consistency2) and prevent significant bioinequivalence.3)

To  achieve  better  prediction  of  drug  product  dissolution  in in vivo conditions, an in vitro dissolution test is conducted under  test  conditions  that  mimic  several  physiological  fluids, such as low sheer stress derived from dissolution medium4,5) and a low volume of test medium.6–8) Other important factors shaping the dissolution profiles are characteristics of the disso-lution  test medium,  such  as pH, buffer  capacity,  and presence or absence of bile components, enzymes, and other compo-nents.9,10)  The  buffer  capacity  is  the  potential  of  a  buffering medium  to  mitigate  changes  in  pH  following  the  addition  of acidic  or  basic.  There  is  a  significant  difference  in  buffer  ca-pacity between human intestinal fluid and dissolution test me-dium.11–14) The buffer capacity of fluids in the stomach, duode-num,  and  jejunum  ranged  from  0.26  to  6.32 µmol/mL/ΔpH  in fasted state, and from 0.78 to 5.98 µmol/mL/ΔpH  in  fed  state in the stomach, duodenum, and proximal and mid/distal jeju-num.15)  Hypo-  and  a-chlorhydric  gastric  conditions  decreased the  buffer  capacities  of  the  fluid  in  the  fasted  stomach  and 

small intestine.16)  In  contrast,  the  buffer  capacities  of  conven-tionally used dissolution test media are: 34 µmol/mL/ΔpH (pH 6.8, United States Phamacopeia (USP) simulated intestinal fluid),11) 35 µmol/mL/ΔpH  (pH  5.0,  fed  state  simulated  gastric fluid),11) and 25 µmol/mL/ΔpH  (pH  5.8,  fed  state  simulated intestinal  fluid).17) Recent studies have proposed the use of dissolution media with  even  lower  buffer  capacities.18,19) Both buffer  capacity  and  ionic  strength  are  reported  to  affect  the dissolution  profiles  of  drug  products  containing  less  soluble active  pharmaceutical  ingredients  (APIs)  because  of  the change  of  surface  pH  and  API  solubility,  although  it  is  con-sidered to have only a slight effect on the dissolution of highly soluble APIs (e.g., BCS class I/III).11,20–22) Thus,  the buffer ca-pacity  of  compendial  dissolution  test  medium  is  significantly higher  than  that  of  intestinal  fluid,  and  the  potential  risk  as-sociated with the use of high buffer capacity medium has been indicated.15)

To  evaluate  the  quality  of  drug  products,  dissolution  tests of  oral  solid  dosage  forms  have  been  conducted  with  three buffering  media  (pH  1.2,  4.0,  and  6.8)  and  purified  water  in Japan.23) The dissolution data showed that some formulations, which included BCS class I or III APIs, showed a much slow-er  dissolution  in  purified  water  (<85% in 30 min) compared with  those  in  three  buffers  (≥ 85% in 30 min). This implied that  the  ionic  strength  and  buffer  capacity  affect  the  dissolu-tion  of  the  formulations  containing  highly  soluble  APIs.  For a  better  understanding  of  the  effect  of  buffer  capacity  on  the dissolution  profile  of  formulations  including  BCS  class  I  or III APIs,  it  is necessary  to evaluate  the dissolution by using a dissolution  test medium with  low  buffer  capacity,  comparable with that of physiological fluids.

In this study, we prepared dissolution test media with a

* To whom correspondence should be addressed.  e-mail: h.yoshida@nihs.go.jp

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low  buffer  capacity  by  simply  diluting  the  media  described in  Japanese  Pharmacopoeia  and  then  adding  sodium  chloride to  maintain  ionic  strength.  By  using metoclopramide  (a  BCS class III drug)24) immediate release products, which show slow dissolution only  in purified water but not  in other buffers,  the usefulness of the diluted compendial dissolution test media as an  alternative  to  biorelevant  media  with  low  buffer  capacity and  the  effect  of  buffer  capacity  on  the  dissolution  of  highly soluble drug products were investigated.

ExperimentalMaterials Three metoclopramide immediate release tab-

lets formulations, Primperan Tablets 5 (Lot#S014G01; Astellas Pharma Inc., Tokyo, Japan), Terperan Tablets (Lot#L166A; ASKA Pharmaceutical. Co., Ltd., Tokyo, Japan), and Meto-clopramide  Tablets  5 mg  [Takata]  (Lot#U001  and  #V004; TAKATA Pharmaceutical Co., Ltd., Saitama, Japan), were obtained from local distributors in Japan. The excipient com-ponents of the products are shown in Table 1. Metoclopramide hydrochloride  was  purchased  from  Sigma-Aldrich  Japan Co. LLC (Tokyo, Japan), pepsin was purchased from Tokyo Chemical  Industry  Co.,  Ltd.  (Tokyo,  Japan),  and  FaSSIF/FeSSIF/FaSSGF  powders  were  purchased  from  Biorelevant.com Ltd. (London, U.K.).

Dissolution Test Media Compendial pH 1.2, 4.0, and 6.8 buffer  solutions  were  prepared  in  accordance  with  the  Japa-nese Pharmacopoeia (JP). Dissolution media with a low buffer 

capacity was prepared by dilution of the compendial dissolu-tion  test  media.  To  maintain  the  ionic  strength  of  a  diluted buffer equal to that in the undiluted dissolution medium, NaCl was  added  to  diluted  dissolution  medium.  A  pH  6.8  buffer solution listed in United States Pharmacopoeia, phosphate and  maleate  buffer,  other  low  buffer  capacity  media,18) were also  prepared.  The  pH,  ionic  strength,  and  composition  of buffer  solutions  used  in  this  study  are  summarized  in  Table 2.  Fasted  State  Simulated  Gastric  Fluid  (FaSSGF),  Fasted State Simulated  Intestinal Fluid  (FaSSIF),  and FaSSGF,  simu-lating  hypochlorhydric  and  achlorhydric  gastric  conditions (FaSSGF(hypo)  and  FaSSGF(achlo))  were  prepared  according to the previous literature.9,25)

Determination of Buffer Capacities of Dissolution Test Media   The  buffer  capacities  of  the  test  media  were  mea-sured in just one pH direction by dropwise addition of either NaOH (for all test solutions) or HCl (for test solutions except for  acidic  buffer  solutions).16) To the dissolution medium (600 mL,  37°C),  0.5 M NaOH or  0.5 M HCl  aqueous  solutions were  added  while  monitoring  the  pH  values  by  using  a  pH meter (LAQUAact D-74, HORIBA, Ltd., Kyoto, Japan). The buffer  capacity  was  calculated  from  the  volume  of  NaOH  or HCl solution added.

Dissolution Tests Dissolution tests were conducted in accordance with the Japanese Pharmaceutical Codex III. Metoclopramide tablets (n = 6) were dissolved in an USP ap-paratus  II  (paddle)  (Toyama  Sangyo  Co.,  Ltd.,  Osaka,  Japan) 

Table  1.  List of Metoclopramide Immediate Release Tablets Formulations Used in the Study

No. Product name Lot No. Manufacturer Excipients

No.1 Primperan® Tablets 5

S014G01 Astellas Pharma Inc.

Lactose hydrate, Corn starch, Hydroxypropylcellulose (HPC), Microcrystal-line  cellulose,  Light  anhydrous  silicic  acid,  Magnesium  stearate  (StMg), Hypromellose, Macrogol, Talc, Precipitated calcium carbonate

No.2 Terperan® Tablets 5 mg

L166A ASKA Pharmaceutical. Co., Ltd.

Carnauba  wax,  Microcrystalline  cellulose,  Titanium  oxide,  Magnesium stearate  (StMg),  Talc,  Corn  starch,  Lactose  hydrate,  Hypromellose, Macrogol6000, Methylcellulose

No.3 Metoclopramide Tablets 5 mg 「Takata」

U001, V004

TAKATA Pharmaceutical Co., Ltd.

Lactose  hydrate,  Microcrystalline  cellulose,  povidone,  Magnesium  stearate (StMg),  Hypromellose,  propylene  glycol,  Titanium  oxide,  Hydroxypropyl-cellulose (HPC), Carnauba wax

Table  2.  pH, Ionic Strength, and Media Composition of Buffer Solution Used in the Study

pH Ionic strength (mmol/L)

Conc. (mmol/L)

HCl NaOH NaCl Na2HPO4 KH2PO4 NaH2PO4C6H8O7

(citric acid)C4H4O4

(maleic acid)

pH 1.2 (JP1) 1.2 115.7 81.49 34.22pH 1.2 (1/15 dilution) + NaCl 2.7 115.7 5.43 110.28pH 1.2 (1/30 dilution) + NaCl 2.6 115.7 2.72 112.99pH 1.2 (1/30 dilution) 2.6 3.9 2.72 1.14pH 4.0 4.0 57.8 19.28 15.36pH 6.8 (JP2) 6.9 50.0 12.50 12.49pH 6.8 (1/2 dilution) + NaCl 6.9 50.0 25.0 6.25 6.25pH 6.8 (1/10 dilution) + NaCl 6.9 50.0 45.0 1.25 1.25pH 6.8 (1/10 dilution) 7.0 5.0 1.25 1.25Purified water 5.7 0.00.2% NaCl 5.7 34.2 34.22pH 6.8 (USP) 6.8 72.4 22.4 50Phospate buffer 6.5 106.9 1.2 101.3 5Maleate buffer 6.4 103.9 12.3 97.7 7

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at 50 rpm in 900 mL volume of test medium at 37 ± 0.5°C. Sampling  for  all  dissolution  tests was  performed  at  5,  10,  15, 30, 45,  and 60 min. At  each  sampling  time, 20 mL of medium was  removed  and  filtered  through  a  0.45 µm  polytetrafluoro-ethylene  (PTFE)  filter  (Chromatodisk  25P,  GL  Sciences  Inc., Tokyo,  Japan),  substituting  20 mL  of  fresh,  prewarmed  me-dium to replace the sample volume removed. pH control was not  performed  during  the  dissolution  test with maleate  buffer solutions.26) The pH values of dissolution test medium before and after the dissolution test were measured.

The concentration of metoclopramide was determined by using  HPLC  system  (Prominence,  Shimadzu  Corporation, Kyoto, Japan). The mobile phase comprised 550 mL of sodium dodecyl  sulfate  (5 mM)  aqueous  solution,  450 mL  aceto-nitrile,  and  3 mL  acetic  acid.  A Mightysil  RP-18  GP  column (150 × 4.6 mm, 5-µm, Kanto Chemical Co., Tokyo, Japan) was used  at  25°C.  The  flow  rate  was  set  to  adjust  the  retention time of metoclopramide to approximately 5 min and the injec-tion volume was 50 µL. Measurements were performed using a detection wavelength of 275 nm.

f2 Calculations Dissolution similarities were statistically evaluated by using the similarity factor (f2) in accordance with the U.S. Food and Drug Administration (FDA) guidance.27)

ResultsBuffer Capacities of Test Media   The buffer capacities of 

various test media resistant to acidic and basic pH change were measured. The buffer capacity in the basic direction for pH 1.2 dissolution  medium  was  approximately  70 mmol/L/ΔpH,  and dilution  of  the  dissolution  medium  decreased  buffer  capacity and  ionic  strength,  depending  on  the  dilution  rate.  Buffer  ca-pacities of 15 and 30-fold diluted pH 1.2 solution were below 5 mmol/L/ΔpH,  which  was  comparable  with  the  buffering capacity  of  human  stomach fluid  reported  previously15) (Table 3). The buffer  capacities  in  the basic direction  for pH 4.0  and 6.8  media  were  approximately  12.8  and  9.8 mmol/L/ΔpH,  re-spectively. A 10-fold dilution of pH 6.8 buffer media yielded a buffer capacity of 1.0 mmol/L/ΔpH. In the pH 1.2 and 6.8 solu-tions, the addition of NaCl increased the ionic strength but did not  alter  the  buffer  capacity.  The  buffer  capacities  of  purified water and 0.2% NaCl aqueous solution were close to zero. The buffer  capacities  of  the  phosphate  and  maleate  buffers  were below  3 mmol/L/ΔpH,  which  were  similar  to  that  of  human intestinal  fluid  from  the  duodenum  or  jejunum.15)  The  buffer capacities in the acidic direction were comparable with in the basic direction for each solution.

Dissolution Profiles in Different pH Buffering Media

The  dissolution  profiles  of  three  metoclopramide  products were  evaluated  (Fig.  1).  Products  No.  1  and  No.  2  showed very rapid dissolution (more than 85% in 15 min) and products No. 3 showed rapid dissolution (more than 85% in 30 min) in  the  pH  1.2,  4.0,  and  6.8  media.  Differences  in  dissolution profiles among three buffer solutions were not observed in any products. In contrast, the delayed dissolution of all the three products  was  observed  when  purified  water  was  used  as  the dissolution test medium. The dissolution rates in 0.2% NaCl solution  were  similarly  slow;  therefore,  low  ionic  strength was not  thought  to be  the cause  for  slow dissolution observed when purified water was used. The pH changes  in dissolution medium  during  the  dissolution  tests  were  observed  in  puri-fied  water  and  0.2% NaCl  aqueous  solution,  but  not  in  other dissolution media (Supplementary Table 1). The bulk pH of purified  water  and  0.2% NaCl  aqueous  solution  increased  by approximately 0.7–1.3 after the dissolution test.The  disintegration  aspects  of  tablets  at  the  initiation  of  the 

dissolution test in pH 6.8 dissolution medium were shown in Fig. 2. Tablets of product No. 1 and 2 disintegrated easily, but a small amount of solid residue was observed from product No. 1. Tablets of product No. 3  tablet did not disintegrate suf-ficiently during the time of dissolution test.

Dissolution Profiles in Low Buffer Capacity Dissolution Media   The  dissolution  profiles  of  the  three  products  were 

Table  3.  Buffer Capacities of Various Dissolution Test Media

pHBuffer capacity

(mmol/L/ΔpH) acidic direction

(mean ± S.D.) bacis direction

pH 1.2 (JP) 1.2 N.D. 67.8 ± 1.1pH 1.2 (1/15 dilution) + NaCl 2.7 N.D. 4.5 ± 0.0pH 1.2 (1/30 dilution) + NaCl 2.6 N.D. 2.0 ± 0.0pH 1.2 (1/30 dilution) 2.6 N.D. 2.3 ± 0.0

pH 4.0 4.0 12.8 ± 0.4 11.4 ± 0.0pH 6.8 (JP) 6.9 9.8 ± 0.0 9.2 ± 0.0pH 6.8 (1/2 dilution) + NaCl 6.9 4.9 ± 0.1 4.8 ± 0.0pH 6.8 (1/10 dilution) + NaCl 6.9 1.0 ± 0.0 1.0 ± 0.0pH 6.8 (1/10 dilution) 7.0 1.0 ± 0.0 1.0 ± 0.0pH 6.8 (USP) 6.8 17.9 ± 0.1 21.4 ± 0.2Phospate buffer 6.5 1.1 ± 0.0 2.3 ± 0.0Maleate buffer 6.4 3.6 ± 0.0 1.5 ± 0.1

Purified water 5.7 0.0 ± 0.0 0.0 ± 0.00.2% NaCl 5.7 0.0 ± 0.0 0.0 ± 0.0N.D., not determined.

Fig.  1.  Dissolution  Profiles  of  Three  Metoclopramide  Formulations  (No.  1,  2,  and  3)  in  pH  1.2,  4.0,  and  6.8  Buffers,  Purified  Water,  and  0.2% Sodium Chloride Solution

Each result represents the mean ± standard deviation (S.D.) of six tablets.

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evaluated  in  acidic  and  neutral  buffer  solutions  and  their  di-luted solutions. The dissolution rates of product No. 1 and No. 2 were very rapid in 15- and 30-fold diluted pH 1.2 media, as well  as  in  the  original  pH  1.2  medium  (Fig.  3).  In  contrast, dissolution  of  product  No.  3  was  delayed  depending  on  dilu-

tion rate and the f2 values were below 50 in 15- and 30-fold diluted  pH  1.2  medium  (Table  4).  The  buffer  capacity  of  the diluted  solution was  low,  but  bulk  pH was  not  changed  in  all of the dissolution media (data not shown).The  effect  of  buffer  capacity  on  the  dissolution  rate  was 

Fig.  2.  Disintegration Aspect of Tablets during the Dissolution Test in pH 6.8 Medium at 5 minWhite arrows indicate the position of tablet. (Color figure can be accessed in the online version.)

Fig.  3.  Effect  of  Buffer  Capacity  on  the  Dissolution  Profiles  of  Three Metoclopramide  Formulations  (No.  1,  2,  and  3)  in  Dissolution Media  with Acidic pHDissolution  tests  were  conducted  with  pH  1.2 medium,  15-fold  diluted  pH  1.2 medium,  and  15-fold  diluted  pH  1.2 medium  containing  sodium  chloride.  Each  result 

represents the mean ± S.D. of six tablets.

Table 4. Dissolution Similarity of Metoclopramide Tablets between pH 1.2 and Other Media

pH 1.2 pH 1.2 (1/15 dilution) + NaCl pH 1.2 (1/30 dilution) + NaCl

No.1 15 min, >85% Similar (15 min, >85%) Similar (15 min, >85%)No.2 15 min, >85% Similar (15 min, >85%) Similar (15 min, >85%)No.3 30 min, >85% Not-similar (f2 = 48.8) Not-similar (f2 = 35.3)

Fig.  4.  Effect of Buffer Capacity on Dissolution Profiles of Three Metoclopramide Formulations (No. 1, 2, and 3) in Dissolution Media with a Neutral pHDissolution tests were conducted with pH 6.8 medium, 2-fold diluted pH 6.8 medium, and 10-fold diluted pH 6.8 medium containing sodium chloride. Each result  rep-

resents the mean ± S.D. of six tablets.

Table 5. Dissolution Similarity of Metoclopramide Tablets between pH 6.8 and Other Media

pH 6.8 pH 6.8 (1/2 dilution) + NaCl pH 6.8 (1/10 dilution) + NaCl

No.1 15 min, >85% Similar (f2 = 56.8) Not-similar (f2 = 36.3)No.2 15 min, >85% Similar (15 min, >85%) Similar (15 min, >85%)No.3 30 min, >85% Not-similar (f2 = 43.6) Not-similar (f2 = 26.2)

668 Vol. 68, No. 7 (2020)Chem. Pharm. Bull.

evaluated  in  compendial  pH 6.8  buffering medium and  its  di-luted  solutions  (Fig.  4).  The  dissolution  of  product No.  2 was slightly retarded in 10-fold diluted pH 6.8 buffer solutions, but exceeded 85% within 15 min in all  three buffering media. The dissolution  rates  of  products  No.  1  and  No.  3  were  strongly affected  by  the  buffer  capacity  of  the  medium.  Product  No. 1 showed very rapid dissolution (>85% in 15 min) in pH 6.8 medium and rapid dissolution (>85% in 30 min) in 2-fold di-luted pH 6.8 medium. In 10-fold diluted pH 6.8 medium, the dissolution of product No. 1 did not exceed 85%, even within 45 min, and the f2 value was 36.3 (Table 5). The dissolution rate of product No. 3 was also delayed in diluted pH 6.8 medi-um and did not reach 85% within 60 min in 10-fold diluted pH 6.8 medium. The dissolution profiles of product No. 3  in both low buffering capacity media were not  judged to be similar  to that in pH 6.8 medium because the f2 values were below 50. Apparent changes  in  the bulk pH during dissolution  test were not observed in the diluted dissolution media (data not shown).The  effect  of  buffer  capacity  on  the  dissolution  rate  was 

evaluated in other low buffer capacity media (Fig. 5). All three products  showed  similar  dissolution  profiles  in  pH  6.8  (JP) and  pH 6.8  (USP)  buffers.  Slower  dissolution  of  products No. 1 and No. 3 was observed in both the phosphate and maleate buffer  solutions  compared  to  that  in  pH  6.8  (JP)  and  pH  6.8 (USP) buffers. The dissolution profiles of product No. 1 and 3 in maleate buffer were  judged  to be dissimilar  to  those  in pH 

6.8 (JP) medium (Table 6). The effect of buffer capacity on the dissolution rate of product No. 2 was limited and the product showed very rapid dissolution (>85%  in 15 min)  in  all  buffer-ing  media.  Although  the  pH  was  not  controlled  during  the dissolution  tests,  the  apparent  bulk  pH  change  in  the maleate and  phosphate  buffers was  not  observed  as well  as  other  dis-solution test media (data not shown).

The dissolution of product No. 3 was evaluated in multiple biorelevant media, which included bile components and/or enzymes to simulate the environment of the stomach and the small intestine in the fasted state (Table 7). Rapid dissolution was  observed  in  FaSSGF  and  FaSSIF,  probably  because  the buffer  capacity was  greater  than  10 mmol/L/ΔpH.  In  contrast, slower dissolution of the formulation was observed in the bio-relevant media  for  simulating  the contents of  the  fasted  stom-ach under hypochlorhydric and achlorhydric conditions with low buffer capacity (Fig. 6).

DiscussionFor  the  appropriate  prediction  of  in vivo dissolution pro-

files, dissolution  tests  in media  that chemically and physically mimic  physiological  conditions  offer  a  promising  approach. This  study  investigated  the  effect  of  the  buffer  capacity  of the  media  on  the  dissolution  rate  of  formulations  of  highly soluble drugs (BCS class III) by using diluted compendial test medium.  The  buffer  capacity  of  compendial  acidic  solution 

Fig.  5.  Effect of Medium Composition on the Dissolution Profiles of Three Metoclopramide Formulations (No. 1, 2, and 3) in Dissolution Media with a Neutral pHDissolution  tests were conducted with pH 6.8 medium (JP), pH 6.8 medium (USP), and phosphate and maleate buffer media. Each  result  represents  the mean ± S.D. of

six tablets.

Table 6. Dissolution Similarity of Metoclopramide Tablets between pH 6.8 (JP) and Other Media

pH 6.8 (JP) pH 6.8 (USP) Phospahate buffer Maleate buffer

No.1 15 min, >85% Similar (15 min, >85%) Similar (f2 = 56.8) Not-similar (f2 = 44.1)No.2 15 min, >85% Similar (15 min, >85%) Similar (15 min, >85%) Similar (15 min, >85%)No.3 30 min, >85% Similar (f2 = 96.0) Similar (f2 = 51.8) Not-similar (f2 = 37.0)

Table  7.  Composition of Biorelevant Media for Simulating the Contents in the Fasted Stomach and Small Intestine

pH Buffer capacity# (mmol/L/ΔpH)

Conc. (mM)

Pepsin (mg/mL)

Sodium taurocholate

Phosphatidyl-choline HCl NaOH NaCl KH2PO4

C4H4O4 (maleic acid)

FaSSGF 1.6 — — 0.08 0.02 q.s. to pH 1.6 — 34.2 — —FaSSIF 6.8 12 — 3 0.75 — 13.8 — 28.7 —FaSSGF(hypo) 5.0 0.8 0.1 0.08 0.02 — q.s. to pH 5.0 15.7 — 1.0FaSSGF(achlo) 7.0 0.7 0.1 0.08 0.02 — q.s. to pH 7.0 7.0 — 3.0#, Buffer capacity values were cited from reference #9 and #25. —, not applicable.

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was proven to be 10-fold higher compared with that of human gastric  fluid,  as  recently  reported.15,16)  Excessive  quantities of  hydrogen  ion  in  the  test  media  would  contribute  to  such high  buffer  capacity.  USP  acidic  buffer  (simulated  gastric fluid,  SGF)  (0.1 N  HCl)  and  FaSSGF  should  also  have  high buffer capacities because their solutions includes a comparable hydrogen  ion  concentration  to  that  of  JP  acidic  buffer  solu-tion (0.081 N HCl).  The  Japanese  guideline  for  bioequivalence studies of generic products specifies a dissolution test medium with  comparably  low  buffer  capacity,  e.g., four-fold diluted McIlvaine  buffer  in  the weak  acid  to  neutral  pH  range.28) Al-though  this medium was  designed  to  evaluate  the  dissolution under  low  buffer  capacity  condition,  the  capacities  is  still much higher  than those of physiological fluid from the duode-num and jejunum.15) Therefore, it is reasonable to apply dis-solution test media other than the commonly used compendial buffer  to  investigate  the  dissolution  of  drug  products  under low buffer capacity. This study also  indicated  that appropriate dilution and NaCl addition into compendial dissolution test medium was an alternative easy preparation method for dis-solution  test  medium  with  intended  low  buffer  capacity  and ionic strength.By using  the example of metoclopramide  tablets,  this  study 

showed  that  there may  be  a  large  effect  of  buffer  capacity  on some highly  soluble APIs. The buffer capacity of  the medium has  been  recognized  as  a  determining  factor  for  the  dissolu-tion  of  less  soluble  drugs,  such  as  carvedilol,11)  quetiapine fumarate,20) and diclofenac sodium.9) The differences were ex-plained  partly  by  possible  changes  in  dissolution medium  pH induced  by  dissolved  drug  and  excipients.29) However, in this study, when using a highly soluble drug, significant changes in the bulk pH were not observed. Cristofoletti et al.  suggested a  local  change  in  surface  pH  (pH0)  around  drug  substances or excipients, due to the lack of conjugative base in a medium with low buffer capacity, was an alternative mechanism for the dissolution changes of poorly soluble drugs.18) As  the effect of buffer capacity on the dissolution rate varied between products No.  1–3,  the  different  formulation  characteristics  among  the products, such as excipients, were inferred as a cause for the delay in dissolution of products No. 1 and 3. Distinctive excip-ients included in products No. 1 or No. 3 were light anhydrous 

silicic acid and precipitated calcium carbonate, or povidone and  propylene  glycol,  respectively.  Some  interaction  between the  excipients  and metoclopramide may  affect  the  dissolution behavior. Indeed, disintegration patterns varied slightly among the three products in the widely used excipient combinations. Tablets  of  product  No.  1  and  No.  3  did  not  disintegrate  suf-ficiently;  therefore,  the  excipient  difference  may  affect  the extent  of  media  inflow  and  outflow  around  the  formulation and  result  in  a  dissolution  difference.  Further  investigation  is required to understand the effect of buffer capacity on the dis-solution by using non-disintegrating tablets.

The slower dissolution of some metoclopramide tablets compared  to  those  in  USP  buffer  or  conventional  biorelevant media were observed in the diluted compendial media. The product No. 3 also showed slow dissolution in the recently proposed biorelevant media. Dissolution of other formulations in the biorelevant media with low buffer capacity would be an interesting  topic  for  further  study. These  results  has  provided two  important  suggestions.  First,  use  of  dissolution  media with  a  sufficiently  low  buffer  capacity,  comparable  to  that  of physiological  fluid,  is  necessary  to  detect  dissolution-delayed products  including  highly  soluble APIs.  Second,  diluted  com-pendial  media  is  a  good  alternative  to  biorelevant  media  to evaluate  the  effect  of  low  buffer  capacity  on  the  dissolution rate. Diluted media are easy to prepare because the simple di-lution and addition of  sodium chloride  to a compendial buffer is  the  only  preparation  required.  Therefore,  diluted  compen-dial medium is useful for routine dissolution tests as it is an easily available dissolution medium with low buffer capacity.

ConclusionThis study showed that media with a buffer capacity compa-

rable with  that  of  physiological  fluid  could  affect  the  dissolu-tion  rate  of  drug  products with  highly  soluble APIs.  The  dis-solution profile obtained from a simple dilution of compendial medium provided information on slower dissolution similar to those obtained in the biorelevant media. This indicated that the  tests  using  lower  buffer  capacity media,  including  diluted compendial  buffer,  rationally  reduce  the  risk  of  different  dis-solution  properties  due  to  the  difference  in  buffer  capacities between compendial medium and physiological fluid.

Acknowledgments This work was partly supported by the Research on Regulatory Harmonization  and Evaluation of Pharmaceuticals, Medical  Devices,  Regenerative  and  Cellular Therapy Products, Gene Therapy Products, and Cosmetics of  the  Japan Agency  for Medical Research  and Development, AMED, under Grant Number JP19mk0101103.

Conflict of Interest  The  authors  declare  no  conflict  of interest.

Supplementary Materials The online version of this ar-ticle contains supplementary materials.

References  1)  Grady  H.,  Elder  D.,  Webster  G.  K.,  Mao  Y.,  Lin  Y.,  Flanagan  T., 

Mann J., Blanchard A., Cohen M. J., Lin J., Kesisoglou F., Hermans A.,  Abend  A.,  Zhang  L.,  Curran  D.,  J. Pharm. Sci., 107, 34–41 (2018).

  2)  Suarez-Sharp S., Cohen M., Kesisoglou F., Abend A., Marroum P., 

Fig.  6.  Effect  of  Medium  Composition  on  Dissolution  Profiles  of  a Metoclopramide Formulation (No. 3) in Biorelevant MediaDissolution  tests  were  conducted  with  Fasted  State  Simulated  Gastric  Fluid 

(FaSSGF),  Fasted  State  Simulated  Intestinal  Fluid  (FaSSIF),  FaSSGF  to  simulate the  hypochlorhydric  and  achlorhydric  gastric  conditions  (FaSSGF(hypo)  and FaSSGF(achlo)). Each result represents the mean ± S.D. of six tablets.

670 Vol. 68, No. 7 (2020)Chem. Pharm. Bull.

Delvadia  P.,  Kotzagiorgis  E.,  Li  M.,  Nordmark  A.,  Bandi  N.,  Sjo-gren E., Babiskin A., Heimbach T., Kijima S., Mandula H., Raines K., Seo P., Zhang X., AAPS J., 20, 93 (2018).

3) Ministry of Health, Labour and Welfare. “The Japanese Pharmaco-poeia,” 17th ed., 2016.

  4)  Bai G., Wang Y., Armenante P. M., Int. J. Pharm., 403, 1–14 (2011).  5)  Morihara  M.,  Aoyagi  N.,  Kaniwa  N.,  Katori  N.,  Kojim  S.,  Drug

Dev. Ind. Pharm., 28, 655–662 (2002).  6)  Ichijo  K.,  Oda  R.,  Ishihara  M.,  Okada  R.,  Moteki  Y.,  Funai  Y., 

Horiuchi T., Kishimoto H., Shirasaka Y., Inoue K., J. Pharm. Sci., 106, 2889–2894 (2017).

7) Takeuchi S., Tsume Y., Amidon G. E., Amidon G. L., J. Pharm. Sci., 103, 3416–3422 (2014).

  8)  Yamashita S., Kataoka M., Higashino H., Sakuma S., Sakamoto T., Uchimaru H., Tsukikawa H., Shiramoto M., Uchiyama H., Tachiki H., Irie S., Pharm. Res., 30, 951–958 (2013).

9) Markopoulos C., Andreas C. J., Vertzoni M., Dressman J., Reppas C., Eur. J. Pharm. Biopharm., 93, 173–182 (2015).

10)  Mudie D. M.,  Samiei N., Marshall D.  J., Amidon G. E., Bergstrom C. A. S., AAPS J., 22, 34 (2020).

11)  Hamed  R.,  Awadallah  A.,  Sunoqrot  S.,  Tarawneh  O.,  Nazzal  S., AlBaraghthi  T.,  Al  Sayyad  J.,  Abbas  A., AAPS PharmSciTech, 17, 418–426 (2016).

12)  Bergstrom  C.  A.,  Holm  R.,  Jorgensen  S.  A.,  Andersson  S.  B.,  Ar-tursson P., Beato S., Borde A., Box K., Brewster M., Dressman J., Feng K.  I.,  Halbert G.,  Kostewicz  E., McAllister M., Muenster U., Thinnes J., Taylor R., Mullertz A., Eur. J. Pharm. Sci., 57, 173–199 (2014).

13) Kalantzi L., Goumas K., Kalioras V., Abrahamsson B., Dressman J. B., Reppas C., Pharm. Res., 23, 165–176 (2006).

14) Persson E. M., Gustafsson A. S., Carlsson A. S., Nilsson R. G., Knutson L., Forsell P., Hanisch G., Lennernas H., Abrahamsson B., Pharm. Res., 22, 2141–2151 (2005).

15) Hens B., Tsume Y., Bermejo M., et al., Mol. Pharm., 14, 4281–4294 (2017).

16)  Litou C., Vertzoni M., Goumas C., Vasdekis V., Xu W., Kesisoglou F., Reppas C., Pharm. Res., 33, 1399–1412 (2016).

17) Jantratid E., Janssen N., Reppas C., Dressman J. B., Pharm. Res., 25, 1663–1676 (2008).

18) Cristofoletti R., Dressman J. B., Eur. J. Pharm. Biopharm., 103, 104–108 (2016).

19)  Tsume Y., Patel S., Fotaki N., Bergstrm C., Amidon G. L., Brasseur J. G., Mudie D. M., Sun D., Bermejo M., Gao P., Zhu W., Sperry D. C., Vertzoni M., Parrott N., Lionberger R., Kambayashi A., Her-mans A., Lu X., Amidon G. E., AAPS J., 20, 100 (2018).

20)  Hamed  R.,  AlJanabi  R.,  Sunoqrot  S.,  Abbas  A.,  Drug Dev. Ind. Pharm., 43, 1330–1342 (2017).

21) Hofsass M. A., Dressman J. B., J. Pharm. Sci., 3, 30298–30299 (2019).

22)  Karkossa F., Klein S., J. Pharm. Pharmacol., 69, 1327–1340 (2017).23) Shibata H., Yoshida H., Izutsu K., Yomota C., Goda Y., Okuda H.,

AAPS Open, 2, 6 (2016).24)  Stosik  A.  G.,  Junginger  H.  E.,  Kopp  S., Midha  K.  K.,  Shah  V.  P., 

Stavchansky S., Dressman J. B., Barends D. M., J. Pharm. Sci., 97, 3700–3708 (2008).

25)  Litou  C.,  Vertzoni  M.,  Xu  W.,  Kesisoglou  F.,  Reppas  C.,  Eur. J. Pharm. Biopharm., 115, 94–101 (2017).

26)  Fuchs  A.,  Leigh  M.,  Kloefer  B.,  Dressman  J.  B.,  Eur. J. Pharm. Biopharm., 94, 229–240 (2015).

27)  US-FDA, “Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms,” 1997.

28)  Ministry of Health, Labour and Welfare,  “Guideline  for Bioequiva-lence Studies of Generic Products,” 2012.

29) Ozturk S. S., Palsson B. O., Donohoe B., Dressman J. B., Pharm. Res., 5, 550–565 (1988).