Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate
Purpose Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular stru...
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| Veröffentlicht in: | Pharmaceutical research 2013-06, Vol.30 (6), p.1628-1641 |
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| creator | John, Christopher T. Xu, Wei Lupton, Lisa K. Harmon, Paul A. |
| description | Purpose
Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.
Methods
Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.
Results
The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.
Conclusions
The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK
a
’s higher than the pH
max
of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride. |
| doi_str_mv | 10.1007/s11095-013-1002-y |
| format | Article |
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Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.
Methods
Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.
Results
The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.
Conclusions
The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK
a
’s higher than the pH
max
of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-013-1002-y</identifier><identifier>PMID: 23512680</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Biochemistry ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Chemical compounds ; Chemistry, Pharmaceutical - methods ; Dissolution ; Excipients - chemistry ; Humidity ; Hydrochloric Acid - chemistry ; Hydrogen-Ion Concentration ; Magnesium Chloride - chemistry ; Medical Law ; Pharmaceutical sciences ; Pharmacology/Toxicology ; Pharmacy ; Research Paper ; Salts - chemistry ; Solubility ; Stearic Acids - chemistry ; Water - chemistry</subject><ispartof>Pharmaceutical research, 2013-06, Vol.30 (6), p.1628-1641</ispartof><rights>Springer Science+Business Media New York 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-75cacafbbe0462a5d484fbaea09b8afa6b9712b1c703ae3cf79aa823b498e6ac3</citedby><cites>FETCH-LOGICAL-c438t-75cacafbbe0462a5d484fbaea09b8afa6b9712b1c703ae3cf79aa823b498e6ac3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11095-013-1002-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11095-013-1002-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23512680$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>John, Christopher T.</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Lupton, Lisa K.</creatorcontrib><creatorcontrib>Harmon, Paul A.</creatorcontrib><title>Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>Purpose
Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.
Methods
Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.
Results
The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.
Conclusions
The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK
a
’s higher than the pH
max
of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.</description><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Chemical compounds</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Dissolution</subject><subject>Excipients - chemistry</subject><subject>Humidity</subject><subject>Hydrochloric Acid - chemistry</subject><subject>Hydrogen-Ion Concentration</subject><subject>Magnesium Chloride - chemistry</subject><subject>Medical Law</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Research Paper</subject><subject>Salts - chemistry</subject><subject>Solubility</subject><subject>Stearic Acids - chemistry</subject><subject>Water - chemistry</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kV9rFDEUxYModq1-AF8k4Isvo_k3k4lv7bq1hYpgLfo23MneqakzyZpkxPk0flWzbBURfMnlwu-cHO4h5ClnLzlj-lXinJm6YlxWZRfVco-seK1lZZj6fJ-smBaqarXiR-RRSreMsZYb9ZAcCVlz0bRsRX6ehTjNI2Tnb-gnhK_jQk8hOUvP1yO9gjGn1_QD7oHvSE96N7q80DDQdZim4Onmh3U7hz4nmgO98NvZIn3j0i6GXYjZBQ_7h4Lf0vwF6bV33-ZC4IgZowtzopthQFv0xfQd3HhMbp7oVUaIkPExeTDAmPDJ3Twm12ebj-vz6vL924v1yWVllWxzpWsLFoa-R6YaAfVWtWroAYGZvoUBmt5oLnpuNZOA0g7aALRC9sq02ICVx-TFwbcELwFT7iaXLI4jeCwhOy6V0UyVWxb0-T_obZijL-kKVTeGaylMofiBsjGkFHHodtFNEJeOs27fXndoryvt7XfRLUXz7M557ifc_lH8rqsA4gCU-5bCMP719X9dfwFEsai-</recordid><startdate>20130601</startdate><enddate>20130601</enddate><creator>John, Christopher T.</creator><creator>Xu, Wei</creator><creator>Lupton, Lisa K.</creator><creator>Harmon, Paul A.</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20130601</creationdate><title>Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate</title><author>John, Christopher T. ; Xu, Wei ; Lupton, Lisa K. ; Harmon, Paul A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-75cacafbbe0462a5d484fbaea09b8afa6b9712b1c703ae3cf79aa823b498e6ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Chemical compounds</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Dissolution</topic><topic>Excipients - chemistry</topic><topic>Humidity</topic><topic>Hydrochloric Acid - chemistry</topic><topic>Hydrogen-Ion Concentration</topic><topic>Magnesium Chloride - chemistry</topic><topic>Medical Law</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Research Paper</topic><topic>Salts - chemistry</topic><topic>Solubility</topic><topic>Stearic Acids - chemistry</topic><topic>Water - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>John, Christopher T.</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Lupton, Lisa K.</creatorcontrib><creatorcontrib>Harmon, Paul A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>John, Christopher T.</au><au>Xu, Wei</au><au>Lupton, Lisa K.</au><au>Harmon, Paul A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2013-06-01</date><risdate>2013</risdate><volume>30</volume><issue>6</issue><spage>1628</spage><epage>1641</epage><pages>1628-1641</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><abstract>Purpose
Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process.
Methods
Binary compacts and “pseudo formulations” are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base.
Results
The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH.
Conclusions
The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK
a
’s higher than the pH
max
of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>23512680</pmid><doi>10.1007/s11095-013-1002-y</doi><tpages>14</tpages></addata></record> |
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| subjects | Biochemistry Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Chemical compounds Chemistry, Pharmaceutical - methods Dissolution Excipients - chemistry Humidity Hydrochloric Acid - chemistry Hydrogen-Ion Concentration Magnesium Chloride - chemistry Medical Law Pharmaceutical sciences Pharmacology/Toxicology Pharmacy Research Paper Salts - chemistry Solubility Stearic Acids - chemistry Water - chemistry |
| title | Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate |
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