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Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.

Abstract BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
PMID
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Authors

Mayor MeshTerms
Keywords

chemical stability

kinetics

pH

preformulation

solid dosage form

stability

stabilization

Journal Title journal of pharmaceutical sciences
Publication Year Start
%A Adams, Monica L.; Sharma, Vijayata; Gokhale, Madhushree; Huang, Yande; Stefanski, Kevin; Su, Ching; Hussain, Munir A.
%T Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.
%J Journal of pharmaceutical sciences, vol. 105, no. 4, pp. 1478-1488
%D 04/2016
%V 105
%N 4
%M eng
%B BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
%P 1478
%L 1488
%Y 10.1016/j.xphs.2015.12.028
%W PHY
%G AUTHOR
%R 2016......105.1478A

@Article{Adams2016,
author="Adams, Monica L.
and Sharma, Vijayata
and Gokhale, Madhushree
and Huang, Yande
and Stefanski, Kevin
and Su, Ching
and Hussain, Munir A.",
title="Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.",
journal="Journal of pharmaceutical sciences",
year="2016",
month="Apr",
day="23",
volume="105",
number="4",
pages="1478--1488",
abstract="BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.",
issn="1520-6017",
doi="10.1016/j.xphs.2015.12.028",
url="http://www.ncbi.nlm.nih.gov/pubmed/26921118",
language="eng"
}

%0 Journal Article
%T Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.
%A Adams, Monica L.
%A Sharma, Vijayata
%A Gokhale, Madhushree
%A Huang, Yande
%A Stefanski, Kevin
%A Su, Ching
%A Hussain, Munir A.
%J Journal of pharmaceutical sciences
%D 2016
%8 Apr 23
%V 105
%N 4
%@ 1520-6017
%G eng
%F Adams2016
%X BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
%U http://dx.doi.org/10.1016/j.xphs.2015.12.028
%U http://www.ncbi.nlm.nih.gov/pubmed/26921118
%P 1478-1488

PT Journal
AU Adams, ML
   Sharma, V
   Gokhale, M
   Huang, Y
   Stefanski, K
   Su, C
   Hussain, MA
TI Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.
SO Journal of pharmaceutical sciences
JI J Pharm Sci
PD Apr
PY 2016
BP 1478
EP 1488
VL 105
IS 4
DI 10.1016/j.xphs.2015.12.028
LA eng
AB BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
ER

PMID- 26921118
OWN - NLM
STAT- In-Process
DA  - 20160329
IS  - 1520-6017 (Electronic)
IS  - 0022-3549 (Linking)
VI  - 105
IP  - 4
DP  - 2016 Apr
TI  - Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral
      Dosage Forms of BMS-779788.
PG  - 1478-88
LID - 10.1016/j.xphs.2015.12.028 [doi]
LID - S0022-3549(16)00265-3 [pii]
AB  - BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic
      imidazole ring. Propensity of the carbinol toward dehydration to yield the
      corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of
      BMS-779788-ALK were observed in excipient compatibility samples. Stability
      studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and
      tablets prepared by both dry and wet granulation processes. An acid-catalyzed
      dehydration mechanism, in which the heterocyclic core contributes resonance
      stability to the cationic intermediate via charge transfer to the imidazole ring,
      was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating
      solution was used to mitigate dehydration. Solution studies revealed degradation 
      of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was
      confirmed by initiating reactions with BMS-779788-ALK over the same pH range.
      Accordingly, a simple reversible scheme can be used to describe reactions
      initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for
      charge delocalization across the heterocycle and probe the degradation mechanism,
      the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity
      for acid-catalyzed dehydration was then evaluated. The acid stability of
      BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity
      liability of the tertiary hydroxyl.
CI  - Copyright (c) 2016 American Pharmacists Association(R). Published by Elsevier
      Inc. All rights reserved.
FAU - Adams, Monica L
AU  - Adams ML
AD  - Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick,
      New Jersey 08903. Electronic address: [email protected]
FAU - Sharma, Vijayata
AU  - Sharma V
AD  - Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick,
      New Jersey 08903.
FAU - Gokhale, Madhushree
AU  - Gokhale M
AD  - Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick,
      New Jersey 08903.
FAU - Huang, Yande
AU  - Huang Y
AD  - Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New
      Brunswick, New Jersey 08903.
FAU - Stefanski, Kevin
AU  - Stefanski K
AD  - Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company,
      Lawrenceville, New Jersey 08648.
FAU - Su, Ching
AU  - Su C
AD  - Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company,
      Lawrenceville, New Jersey 08648.
FAU - Hussain, Munir A
AU  - Hussain MA
AD  - Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick,
      New Jersey 08903.
LA  - eng
PT  - Journal Article
DEP - 20160223
PL  - United States
TA  - J Pharm Sci
JT  - Journal of pharmaceutical sciences
JID - 2985195R
SB  - IM
OTO - NOTNLM
OT  - chemical stability
OT  - kinetics
OT  - pH
OT  - preformulation
OT  - solid dosage form
OT  - stability
OT  - stabilization
EDAT- 2016/02/28 06:00
MHDA- 2016/02/28 06:00
CRDT- 2016/02/28 06:00
PHST- 2015/09/11 [received]
PHST- 2015/11/30 [revised]
PHST- 2015/12/18 [accepted]
PHST- 2016/02/23 [aheadofprint]
AID - S0022-3549(16)00265-3 [pii]
AID - 10.1016/j.xphs.2015.12.028 [doi]
PST - ppublish
SO  - J Pharm Sci. 2016 Apr;105(4):1478-88. doi: 10.1016/j.xphs.2015.12.028. Epub 2016 
      Feb 23.

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