Physicochemical stability of phospholipid-dispersed suspensions of crystalline itraconazole
The physicochemical stability of an aqueous, phospholipid-based dispersion of itraconazole microcrystals was studied as a model water-insoluble drug suspension. The particle size, phospholipid concentrations, free fatty acid (FFA) content, pH, and zeta potential of two test suspensions were followed...
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| Veröffentlicht in: | European journal of pharmaceutics and biopharmaceutics 2008-08, Vol.69 (3), p.1104-1113 |
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| container_title | European journal of pharmaceutics and biopharmaceutics |
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| creator | Werling, Jane Graham, Sabine Owen, Heather Nair, Lakshmy Gonyon, Thomas Carter, Phillip W. |
| description | The physicochemical stability of an aqueous, phospholipid-based dispersion of itraconazole microcrystals was studied as a model water-insoluble drug suspension. The particle size, phospholipid concentrations, free fatty acid (FFA) content, pH, and zeta potential of two test suspensions were followed over 63 days at 5 and 40
°C storage conditions. Hydrolysis of a control suspension containing Lipoid E80 led to rapid FFA formation, pH drop, and subsequent particle aggregation. In the second suspension, sodium oleate used in conjunction with Lipoid E80 significantly enhanced the suspension physicochemical stability. Oleate anions effectively (1) increased the anionic charge of the phospholipid surface layer, (2) buffered the suspension near pH 7, and (3) reduced the specific production of oleic acid as a phosphatidylcholine (PC) degradant. The observed hydrolysis rate constants
k
obs
∼
2
×
10
−7 (Lipoid only) and
k
obs
∼
5
×
10
−8 (Lipoid and oleate) were consistent with the pH dependent behavior reported for saturated soybean PC solutions. Mechanistically, FFA formed initially in the control suspension partitioned to the aqueous phase with limited influence on the phospholipid microenvironment at the itraconazole particle surface. Phospholipid stabilization of water-insoluble drugs was demonstrated with clear benefits from fatty acid anions as co-additives to influence the surface microenvironment, reduce hydrolysis kinetics, and enhance suspension physicochemical stability. |
| doi_str_mv | 10.1016/j.ejpb.2008.01.030 |
| format | Article |
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°C storage conditions. Hydrolysis of a control suspension containing Lipoid E80 led to rapid FFA formation, pH drop, and subsequent particle aggregation. In the second suspension, sodium oleate used in conjunction with Lipoid E80 significantly enhanced the suspension physicochemical stability. Oleate anions effectively (1) increased the anionic charge of the phospholipid surface layer, (2) buffered the suspension near pH 7, and (3) reduced the specific production of oleic acid as a phosphatidylcholine (PC) degradant. The observed hydrolysis rate constants
k
obs
∼
2
×
10
−7 (Lipoid only) and
k
obs
∼
5
×
10
−8 (Lipoid and oleate) were consistent with the pH dependent behavior reported for saturated soybean PC solutions. Mechanistically, FFA formed initially in the control suspension partitioned to the aqueous phase with limited influence on the phospholipid microenvironment at the itraconazole particle surface. Phospholipid stabilization of water-insoluble drugs was demonstrated with clear benefits from fatty acid anions as co-additives to influence the surface microenvironment, reduce hydrolysis kinetics, and enhance suspension physicochemical stability.</description><identifier>ISSN: 0939-6411</identifier><identifier>EISSN: 1873-3441</identifier><identifier>DOI: 10.1016/j.ejpb.2008.01.030</identifier><identifier>PMID: 18406586</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Antifungal Agents - administration & dosage ; Antifungal Agents - chemistry ; Biological and medical sciences ; Chemical Phenomena ; Chemistry, Physical ; Crystalline suspensions ; Crystallization ; Drug Stability ; Electrochemistry ; Excipients ; Fatty Acids, Nonesterified - chemistry ; General pharmacology ; Hydrogen-Ion Concentration ; Hydrolysis ; Itraconazole ; Itraconazole - administration & dosage ; Itraconazole - chemistry ; Lecithins - chemistry ; Medical sciences ; Oleate ; Particle Size ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. Drug treatments ; Phospholipid ; Phospholipids - chemistry ; Physicochemical stability ; Suspensions</subject><ispartof>European journal of pharmaceutics and biopharmaceutics, 2008-08, Vol.69 (3), p.1104-1113</ispartof><rights>2008 Elsevier B.V.</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-16d2ccdf357a2dfe2d66c72ffa850ec9bee212d34cbed6ef60d392ab7c22c4ff3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejpb.2008.01.030$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20593546$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18406586$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Werling, Jane</creatorcontrib><creatorcontrib>Graham, Sabine</creatorcontrib><creatorcontrib>Owen, Heather</creatorcontrib><creatorcontrib>Nair, Lakshmy</creatorcontrib><creatorcontrib>Gonyon, Thomas</creatorcontrib><creatorcontrib>Carter, Phillip W.</creatorcontrib><title>Physicochemical stability of phospholipid-dispersed suspensions of crystalline itraconazole</title><title>European journal of pharmaceutics and biopharmaceutics</title><addtitle>Eur J Pharm Biopharm</addtitle><description>The physicochemical stability of an aqueous, phospholipid-based dispersion of itraconazole microcrystals was studied as a model water-insoluble drug suspension. The particle size, phospholipid concentrations, free fatty acid (FFA) content, pH, and zeta potential of two test suspensions were followed over 63 days at 5 and 40
°C storage conditions. Hydrolysis of a control suspension containing Lipoid E80 led to rapid FFA formation, pH drop, and subsequent particle aggregation. In the second suspension, sodium oleate used in conjunction with Lipoid E80 significantly enhanced the suspension physicochemical stability. Oleate anions effectively (1) increased the anionic charge of the phospholipid surface layer, (2) buffered the suspension near pH 7, and (3) reduced the specific production of oleic acid as a phosphatidylcholine (PC) degradant. The observed hydrolysis rate constants
k
obs
∼
2
×
10
−7 (Lipoid only) and
k
obs
∼
5
×
10
−8 (Lipoid and oleate) were consistent with the pH dependent behavior reported for saturated soybean PC solutions. Mechanistically, FFA formed initially in the control suspension partitioned to the aqueous phase with limited influence on the phospholipid microenvironment at the itraconazole particle surface. Phospholipid stabilization of water-insoluble drugs was demonstrated with clear benefits from fatty acid anions as co-additives to influence the surface microenvironment, reduce hydrolysis kinetics, and enhance suspension physicochemical stability.</description><subject>Antifungal Agents - administration & dosage</subject><subject>Antifungal Agents - chemistry</subject><subject>Biological and medical sciences</subject><subject>Chemical Phenomena</subject><subject>Chemistry, Physical</subject><subject>Crystalline suspensions</subject><subject>Crystallization</subject><subject>Drug Stability</subject><subject>Electrochemistry</subject><subject>Excipients</subject><subject>Fatty Acids, Nonesterified - chemistry</subject><subject>General pharmacology</subject><subject>Hydrogen-Ion Concentration</subject><subject>Hydrolysis</subject><subject>Itraconazole</subject><subject>Itraconazole - administration & dosage</subject><subject>Itraconazole - chemistry</subject><subject>Lecithins - chemistry</subject><subject>Medical sciences</subject><subject>Oleate</subject><subject>Particle Size</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Phospholipid</subject><subject>Phospholipids - chemistry</subject><subject>Physicochemical stability</subject><subject>Suspensions</subject><issn>0939-6411</issn><issn>1873-3441</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD2P1DAQhi0E4paDP0CB0kCX4I_ESSQadOJLOgkKqCgsZzzWeuWNgyd70vLrcbQr6ChGM8Xzvho9jL0UvBFc6LeHBg_L1EjOh4aLhiv-iO3E0Ktata14zHZ8VGOtWyFu2DOiA-e87bvhKbsRQ8t1N-gd-_ltf6YACfZ4DGBjRaudQgzruUq-WvaJysSwBFe7QAtmQlfRqVwzhTTTRkE-l1SMYcYqrNlCmu3vFPE5e-JtJHxx3bfsx8cP3-8-1_dfP325e39fQ9vxtRbaSQDnVddb6TxKpzX00ns7dBxhnBClkE61MKHT6DV3apR26kFKaL1Xt-zNpXfJ6dcJaTXHQIAx2hnTiYwe1aB6oQsoLyDkRJTRmyWHo81nI7jZlJqD2ZSaTanhwhSlJfTq2n6ajuj-Ra4OC_D6ClgqBn22MwT6y0nejaprN-7dhcPi4iFgNgQBZ0AXMsJqXAr_--MPGgiYlA</recordid><startdate>20080801</startdate><enddate>20080801</enddate><creator>Werling, Jane</creator><creator>Graham, Sabine</creator><creator>Owen, Heather</creator><creator>Nair, Lakshmy</creator><creator>Gonyon, Thomas</creator><creator>Carter, Phillip W.</creator><general>Elsevier B.V</general><general>Elsevier Science</general><scope>IQODW</scope><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></search><sort><creationdate>20080801</creationdate><title>Physicochemical stability of phospholipid-dispersed suspensions of crystalline itraconazole</title><author>Werling, Jane ; Graham, Sabine ; Owen, Heather ; Nair, Lakshmy ; Gonyon, Thomas ; Carter, Phillip W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-16d2ccdf357a2dfe2d66c72ffa850ec9bee212d34cbed6ef60d392ab7c22c4ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antifungal Agents - administration & dosage</topic><topic>Antifungal Agents - chemistry</topic><topic>Biological and medical sciences</topic><topic>Chemical Phenomena</topic><topic>Chemistry, Physical</topic><topic>Crystalline suspensions</topic><topic>Crystallization</topic><topic>Drug Stability</topic><topic>Electrochemistry</topic><topic>Excipients</topic><topic>Fatty Acids, Nonesterified - chemistry</topic><topic>General pharmacology</topic><topic>Hydrogen-Ion Concentration</topic><topic>Hydrolysis</topic><topic>Itraconazole</topic><topic>Itraconazole - administration & dosage</topic><topic>Itraconazole - chemistry</topic><topic>Lecithins - chemistry</topic><topic>Medical sciences</topic><topic>Oleate</topic><topic>Particle Size</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Phospholipid</topic><topic>Phospholipids - chemistry</topic><topic>Physicochemical stability</topic><topic>Suspensions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Werling, Jane</creatorcontrib><creatorcontrib>Graham, Sabine</creatorcontrib><creatorcontrib>Owen, Heather</creatorcontrib><creatorcontrib>Nair, Lakshmy</creatorcontrib><creatorcontrib>Gonyon, Thomas</creatorcontrib><creatorcontrib>Carter, Phillip W.</creatorcontrib><collection>Pascal-Francis</collection><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>European journal of pharmaceutics and biopharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Werling, Jane</au><au>Graham, Sabine</au><au>Owen, Heather</au><au>Nair, Lakshmy</au><au>Gonyon, Thomas</au><au>Carter, Phillip W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Physicochemical stability of phospholipid-dispersed suspensions of crystalline itraconazole</atitle><jtitle>European journal of pharmaceutics and biopharmaceutics</jtitle><addtitle>Eur J Pharm Biopharm</addtitle><date>2008-08-01</date><risdate>2008</risdate><volume>69</volume><issue>3</issue><spage>1104</spage><epage>1113</epage><pages>1104-1113</pages><issn>0939-6411</issn><eissn>1873-3441</eissn><abstract>The physicochemical stability of an aqueous, phospholipid-based dispersion of itraconazole microcrystals was studied as a model water-insoluble drug suspension. The particle size, phospholipid concentrations, free fatty acid (FFA) content, pH, and zeta potential of two test suspensions were followed over 63 days at 5 and 40
°C storage conditions. Hydrolysis of a control suspension containing Lipoid E80 led to rapid FFA formation, pH drop, and subsequent particle aggregation. In the second suspension, sodium oleate used in conjunction with Lipoid E80 significantly enhanced the suspension physicochemical stability. Oleate anions effectively (1) increased the anionic charge of the phospholipid surface layer, (2) buffered the suspension near pH 7, and (3) reduced the specific production of oleic acid as a phosphatidylcholine (PC) degradant. The observed hydrolysis rate constants
k
obs
∼
2
×
10
−7 (Lipoid only) and
k
obs
∼
5
×
10
−8 (Lipoid and oleate) were consistent with the pH dependent behavior reported for saturated soybean PC solutions. Mechanistically, FFA formed initially in the control suspension partitioned to the aqueous phase with limited influence on the phospholipid microenvironment at the itraconazole particle surface. Phospholipid stabilization of water-insoluble drugs was demonstrated with clear benefits from fatty acid anions as co-additives to influence the surface microenvironment, reduce hydrolysis kinetics, and enhance suspension physicochemical stability.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>18406586</pmid><doi>10.1016/j.ejpb.2008.01.030</doi><tpages>10</tpages></addata></record> |
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| ispartof | European journal of pharmaceutics and biopharmaceutics, 2008-08, Vol.69 (3), p.1104-1113 |
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| subjects | Antifungal Agents - administration & dosage Antifungal Agents - chemistry Biological and medical sciences Chemical Phenomena Chemistry, Physical Crystalline suspensions Crystallization Drug Stability Electrochemistry Excipients Fatty Acids, Nonesterified - chemistry General pharmacology Hydrogen-Ion Concentration Hydrolysis Itraconazole Itraconazole - administration & dosage Itraconazole - chemistry Lecithins - chemistry Medical sciences Oleate Particle Size Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Phospholipid Phospholipids - chemistry Physicochemical stability Suspensions |
| title | Physicochemical stability of phospholipid-dispersed suspensions of crystalline itraconazole |
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