Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt
Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The...
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Veröffentlicht in: | Molecular pharmaceutics 2019-04, Vol.16 (4), p.1669-1677 |
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description | Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, pK a = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid–liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 h in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na. |
doi_str_mv | 10.1021/acs.molpharmaceut.9b00006 |
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However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, pK a = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid–liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 h in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na.</description><identifier>ISSN: 1543-8384</identifier><identifier>EISSN: 1543-8392</identifier><identifier>DOI: 10.1021/acs.molpharmaceut.9b00006</identifier><identifier>PMID: 30794420</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acids - chemistry ; Chemical Precipitation ; Crystallization ; Diclofenac - chemistry ; Drug Compounding ; Hydrogen-Ion Concentration ; Salts - chemistry ; Solubility</subject><ispartof>Molecular pharmaceutics, 2019-04, Vol.16 (4), p.1669-1677</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a455t-4581d9fdf2678d8a8108565bf79dd0b69faffd634b003614be4f3faa6259c90d3</citedby><cites>FETCH-LOGICAL-a455t-4581d9fdf2678d8a8108565bf79dd0b69faffd634b003614be4f3faa6259c90d3</cites><orcidid>0000-0001-5652-1786</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.9b00006$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.9b00006$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2764,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30794420$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oki, Jumpei</creatorcontrib><creatorcontrib>Watanabe, Daiju</creatorcontrib><creatorcontrib>Uekusa, Taiga</creatorcontrib><creatorcontrib>Sugano, Kiyohiko</creatorcontrib><title>Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt</title><title>Molecular pharmaceutics</title><addtitle>Mol. Pharmaceutics</addtitle><description>Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, pK a = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid–liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 h in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na.</description><subject>Acids - chemistry</subject><subject>Chemical Precipitation</subject><subject>Crystallization</subject><subject>Diclofenac - chemistry</subject><subject>Drug Compounding</subject><subject>Hydrogen-Ion Concentration</subject><subject>Salts - chemistry</subject><subject>Solubility</subject><issn>1543-8384</issn><issn>1543-8392</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkMtOwzAQRS0EoqXwCyjs2LTYie3ay6o8pSKQCuvI8YO6SuJgxwv-HoeWSuyYzYw1915rDgBXCM4QzNGNkGHWuLrbCN8IqWM_4xVMRY_AGBFcTFnB8-PDzPAInIWwhTDHJC9OwaiAc45xDsdg_azlRrQ2NJkz2Tp22gfRRy9669rh3XkdwjDbNru1Ibg6_qxevZNpM7gW0iors1sfP7K1qPtzcGJEHfTFvk_A-_3d2_Jxunp5eFouVlOBCemnmDCkuFEmp3OmmGAIMkJJZeZcKVhRboQxihY43VZQhCuNTWGEoDnhkkNVTMD1Lrfz7jPq0JeNDVLXtWi1i6HMESOEMkpRkvKdVHoXgtem7LxthP8qESwHpmViWv5hWu6ZJu_l_ptYNVodnL8Qk4DsBEPG1kXfpqv_EfwNgUGL1w</recordid><startdate>20190401</startdate><enddate>20190401</enddate><creator>Oki, Jumpei</creator><creator>Watanabe, Daiju</creator><creator>Uekusa, Taiga</creator><creator>Sugano, Kiyohiko</creator><general>American Chemical Society</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>7X8</scope><orcidid>https://orcid.org/0000-0001-5652-1786</orcidid></search><sort><creationdate>20190401</creationdate><title>Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt</title><author>Oki, Jumpei ; Watanabe, Daiju ; Uekusa, Taiga ; Sugano, Kiyohiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a455t-4581d9fdf2678d8a8108565bf79dd0b69faffd634b003614be4f3faa6259c90d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acids - chemistry</topic><topic>Chemical Precipitation</topic><topic>Crystallization</topic><topic>Diclofenac - chemistry</topic><topic>Drug Compounding</topic><topic>Hydrogen-Ion Concentration</topic><topic>Salts - chemistry</topic><topic>Solubility</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oki, Jumpei</creatorcontrib><creatorcontrib>Watanabe, Daiju</creatorcontrib><creatorcontrib>Uekusa, Taiga</creatorcontrib><creatorcontrib>Sugano, Kiyohiko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oki, Jumpei</au><au>Watanabe, Daiju</au><au>Uekusa, Taiga</au><au>Sugano, Kiyohiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt</atitle><jtitle>Molecular pharmaceutics</jtitle><addtitle>Mol. Pharmaceutics</addtitle><date>2019-04-01</date><risdate>2019</risdate><volume>16</volume><issue>4</issue><spage>1669</spage><epage>1677</epage><pages>1669-1677</pages><issn>1543-8384</issn><eissn>1543-8392</eissn><abstract>Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, pK a = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid–liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 h in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>30794420</pmid><doi>10.1021/acs.molpharmaceut.9b00006</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-5652-1786</orcidid></addata></record> |
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subjects | Acids - chemistry Chemical Precipitation Crystallization Diclofenac - chemistry Drug Compounding Hydrogen-Ion Concentration Salts - chemistry Solubility |
title | Mechanism of Supersaturation Suppression in Dissolution Process of Acidic Drug Salt |
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