Interactions of artefenomel (OZ-439) with milk during digestion

insights into digestion-driven solubilization and polymorphic transformations

Malinda Salim, Jamal Khan, Gisela Ramirez, Andrew J. Clulow, Adrian Hawley, Hanu Ramachandruni, Ben J. Boyd

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and re-crystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for co-administration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.

Original languageEnglish
Pages (from-to)3535-3544
Number of pages10
JournalMolecular Pharmaceutics
Volume15
Issue number8
DOIs
Publication statusPublished - 22 Jun 2018

Cite this

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title = "Interactions of artefenomel (OZ-439) with milk during digestion: insights into digestion-driven solubilization and polymorphic transformations",
abstract = "Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and re-crystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for co-administration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.",
author = "Malinda Salim and Jamal Khan and Gisela Ramirez and Clulow, {Andrew J.} and Adrian Hawley and Hanu Ramachandruni and Boyd, {Ben J.}",
year = "2018",
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language = "English",
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Interactions of artefenomel (OZ-439) with milk during digestion : insights into digestion-driven solubilization and polymorphic transformations. / Salim, Malinda; Khan, Jamal; Ramirez, Gisela; Clulow, Andrew J.; Hawley, Adrian; Ramachandruni, Hanu; Boyd, Ben J.

In: Molecular Pharmaceutics, Vol. 15, No. 8, 22.06.2018, p. 3535-3544.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Interactions of artefenomel (OZ-439) with milk during digestion

T2 - insights into digestion-driven solubilization and polymorphic transformations

AU - Salim, Malinda

AU - Khan, Jamal

AU - Ramirez, Gisela

AU - Clulow, Andrew J.

AU - Hawley, Adrian

AU - Ramachandruni, Hanu

AU - Boyd, Ben J.

PY - 2018/6/22

Y1 - 2018/6/22

N2 - Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and re-crystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for co-administration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.

AB - Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and re-crystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for co-administration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.

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U2 - 10.1021/acs.molpharmaceut.8b00541

DO - 10.1021/acs.molpharmaceut.8b00541

M3 - Article

VL - 15

SP - 3535

EP - 3544

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 8

ER -