Crystallization and Polymorphs: Impact on Performance of

Malaria and HIV drugs

Crystal Crystal BrickhouseBrickhouse, Adrian Williams, and Dr. Joseph , Adrian Williams, and Dr. Joseph FortunakFortunak

Background InformationBackground InformationBioavailibility measures the Bioavailibility measures the quantity of a drug in systemic quantity of a drug in systemic circulation circulation vsvs time (see Fig.1)time (see Fig.1)Drugs must dissolve and be Drugs must dissolve and be absorbed (mainly in the absorbed (mainly in the stomach) to be orally stomach) to be orally bioavailablebioavailableEvery drug has a unique Every drug has a unique window of absorption (WOA) window of absorption (WOA) which represents the time over which represents the time over which its best absorbed (see which its best absorbed (see Fig. 2)Fig. 2)Relative bioavailibility of drugs Relative bioavailibility of drugs change dramatically if their change dramatically if their dissolution profile is altered dissolution profile is altered because it will affect because it will affect absorption within the WOAabsorption within the WOA

Fig. 1 Bioavailability Curve

Fig. 2 Window of Absorption Curve

Stages of a medicine's life in the bodyStages of a medicine's life in the body

AbsorptionAbsorption--Medicines can enter the Medicines can enter the body in many different ways, and body in many different ways, and they are absorbed when they travel they are absorbed when they travel from the site of administration into from the site of administration into the body's circulation the body's circulation DistributionDistribution--Most often, the Most often, the bloodstream carries medicines bloodstream carries medicines throughout the body throughout the body MetabolismMetabolism--The breaking down of a The breaking down of a drug molecule usually involves two drug molecule usually involves two steps that take place mostly in the steps that take place mostly in the body's chemical processing plant, body's chemical processing plant, the liver the liver ExcretionExcretion--Once liver enzymes are Once liver enzymes are finished working on a medicine, the finished working on a medicine, the nownow--inactive drug undergoes the inactive drug undergoes the final stage of its time in the body, final stage of its time in the body, excretionexcretion, as it exits via the urine or , as it exits via the urine or feces feces

Purpose of Research ProjectPurpose of Research ProjectA solid form of a drug can have very different solubility and dissolution profiles, depending upon the crystalline form it is inthe more stable a crystalline form of a drug, the less soluble it is and this decrease in solubility can affect bioavailability

Most critical malaria drugs have not been studied to characterize their crystalline polymorphs, solubility and intrinsic dissolution and this is the subject of our work

Drugs UsedDrugs Used

AmodiaquineArtesunate

Lumefantrine

Dihydroartemisinin Artemether Tenofovir Disoproxil Fumarate

N

N N

N

O PO

OO

O O

OOOO

NH2

COOH

COOH

O

OHH

OO

HCH 3

O

CH 3 H

CH 3H

ONa

O

O

Experimental MethodExperimental MethodWe identified potentially useful solventsSolutions were prepared by dissolving these drugs and allowing them to crystallize either rapidly (under kinetic control) or slowly (under thermodynamic control)Some drugs provided more than one crystalline form, displaying differences in physical and spectroscopic behaviorResults are being analyzed through single-crystal X-ray analysis and X-ray powder diffraction, melting point, Infared (IR) and proton (1H) NMR analysis

ResultsResultsTenofovir Disoproxil Fumarate (TDF) is a drug prepared in a salt form (containing a counterion)

This drug recrystallized from 2-propanol as a different salt form (hemi-fumarate rather than a stoichiometric fumaric acid salt) than TDF itself

Molecular weight: 635.52 g/mol

M.p. of a fumaric acid: 287 °C

M.p. of a hemifumerate: 100° C

Results (cont.)Results (cont.)

NMR ANALYSIS NMR ANALYSIS HemifumerateHemifumerate vsvs FumarateFumarate

The peak on the The peak on the hemifumaratehemifumarate is half the is half the value of the value of the fumaratefumarateThis indicates that the This indicates that the hemifumaratehemifumarate gives gives a 1:2 ratio for the a 1:2 ratio for the fumaricfumaric acid to acid to tenofovirtenofovir while the while the fumaratefumarate gives a 1:1 ratio gives a 1:1 ratio

Results, cont.Results, cont.

Crystal xCrystal x--rays and polymorphsrays and polymorphs--still still awaiting resultsawaiting results

Discussion/ConclusionsDiscussion/ConclusionsBy performing this research, hopefully I have created a more bioavailable form of some if not all of these drugs. Through the obtained results, I will assure that the procedures used by malaria drug manufacturers always supply the same crystalline form. Ultimately, my research will be transferred to manufacturers of malaria drugs in India and China through the Clinton Health Care Access Initiative.

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AcknowledgmentsAcknowledgments

Amgen Scholars ProgramAmgen Scholars ProgramDr. Fortunak and Howard University Dr. Fortunak and Howard University Graduate StudentsGraduate Students