Ongoing Projects Curcumin–Pyrogallol Polypill

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Solid State Forms of Curcumin

Temozolomide Stability and Dissolution

Screening and Characterization of novel solid state forms of less soluble drugs and

bioactive agents

Curcumin (Diferuloylmethane ) A Wonder Spice

O OH

OHOH

OMeOMe

CURCUMIN

Principal curcuminoid of popular Indian spice turmeric (haldi).

Pharmacokinetics and biological activity of curcumin tested in cancer

patients at 0.2-2 g/d dose in Phase I clinical for 3 months

Chemo-preventive and chemotherapeutic activity in animal and human

trials convincingly demonstrated

Curcumin is totally safe even at high doses of up to 12 g/day

Can modulate multiple cellular targets and gene regulation

Not approved as approved drug?

Stable in acidic medium, but decomposes at alkaline pH

Very low solubility in water (7-8 mg/L) at acidic or neutral pH

More soluble in alkaline medium, but decomposes to 90% extent within 30

min in 0.1 M phosphate buffer at pH 7.2 and 37 °C

Poor bioavailability due to rapid metabolism in liver and intestinal wall

Temozolomide N

NN

N

O

ONH

2

N

Temozolomide

Chemotherapy for glioblastoma multiforme (GBM)

Primary malignant brain and CNS tumor

Approved for treatment of malignant glioma in US

and EU in 1999. Patent expires in 2014

First drug licensed for treatment of malignant glioma

in past 30 years

Temodar/ Temodal is Schering-Plough molecule

Discovered at Aston University in 1980s

TMZ prodrug. Active species is MTIC (CH3N2+)

White samples of temozolomide stored at 45% RH

turned pink after 24 hours and the material was

distinctly tan after 4 days indicating decomposition

There is a need to make stable Temozolomide form

Loop diuretic drug commonly used in the

treatment of hypertension and edema.

BCS class IV drug. Solubility 6 mg/L in water

and permeability log Pow 1.4

The highest dose strength of Furosemide is 80

mg, i.e. Do number of 53

Cl

SO2NH

2

HOOC

NH

O

FUROSEMIDE

Antimycotic imidazole effective against a

wide range of fungal pathogens

Diverse biological actions

Effectively and rapidly inhibits growth of

Plasmodium falciparum strains in vitro

Active against chloroquine sensitive strains

and functions as effective antimalarial

But CLT has poor aqueous solubility (< 1

mg/L) and is hydrolyzed in acidic medium

N

N

Cl

CLOTRIMAZOLE

N

F

N

NH

O

COOH

NORFLOXACIN

N

F

N

NH

O

COOH

CIPROFLOXACIN

Broad-spectrum antibacterial agents

Currently marketed solid dose of Norfloxacin

is BCS Class IV

Fluoroquinone–COOH cocrystals of improved

solubility and stability crystallized

Biopharmaceutics Classification System

The Biopharmaceutics Classification System (BCS) is a guide to predict the intestinal drug absorption provided by US-FDA

Three polymorphs crystallized, form I

(P2/n), Form II (Pca21) and Form III (Pbca)

Amorphous form obtained by cooling

of melt

Cur•Resorcinol and Cur•Pyrogallol

cocrystals characterized

Form I

Form II Form III

DSC of curcumin polymorphs Dissolution rate in 40% EtOH-water at 37 °C

Curcumin•Resorcinol

Curcumin•Pyrogallol

Powder dissolution curves for curcumin Form 1 (●), cocrystal 1a (■) and cocrystal 1b (▲)

Intrinsic dissolution rate of curcumin Form 1 (●), curcumin–resorcinol (■) and curcumin–pyrogallol (▲) in 40% EtOH-water at 37 °C.

Amla – A Wonder Berry

Active component is Pyrogallol

Potential as nontoxic anti-cancer agent

Apoptosis of neoplastic cells. Normal cells

unaffected

Cocrystals of Curcumin with Pyrogallol and Resorcinol

Stability wise CUR-PYR and CUR-RES >

fast dissolving polymorph 2 >> amorphous

powder in EtOH-water medium

Commercial curcumin most stable but

least soluble

Can CUR-PYR lead to a new anti-cancer

combo drug?

From Indian Medicinal Plants to a New Drug

Pyrogallol

Anti-proliferative on human cancer cell lines. Cytotoxicity and mutagenicity

in E coli strains

Formation of ROS OH· radical cell death

It increased intracellular O2- levels & decreased GSH content in HeLa cells.

It decreased growth of Calu-6 cells (lung cancer) in dose- and time-

dependent manner at M conc.

Chem. Comm. 2011, 47, 5013-5015 Cryst. Growth Des. 2011, 11, 4135-4145

Stable Temozolomide Cocrystals

N

NN

NN

CH3

ONH

2

O

NH2

N

O

NH2

NH

AIC, hydrolyzed TMZ

Temozolomide, TMZ

N

NN

NN

CH3

ONH

2

H HH2O

+ CO2

N

NN

NN

CH3

ONH

2H

H

MTIC

+DNA

- N2

Methylated DNA

CH3

N N+

With the knowledge that TMZ is stable at acidic pH <5 but labile at pH >7, the

drug molecule was co-crystallized with GRAS organic acids as pH adjusters to

improve API stability

OO

O O

H

H

OO

H

O O

H

O

O

OH

H

OO

H

O O

H

OH O

O

NH

H

H

O

OH

O

O H

OH

OH

OO

H

OO

H

O O

H NH2

OO

H

OH

OO

H

H

O

O HCH

3

O

O H

Acetic acid (AA)

Oxalic acid (OA) Succnic acid (SA) Salicylic acid (SAC) DL-Malic acid (MA) Anthranilic acid (ANA)

DL-Tartaric acid (TA) Formic acid (FA)

Cinnamic acid (CA) Fumaric acid (FUA) p-Aminobenzoic acid (PABA) p-Hydroxybenzoic acid (PHBA)

TMZ·Succinic acid (1:0.5) pKa = 4.2, 5.6

TMZ·Salicylic acid (1:1) pKa = 2.9

TMZ·Oxalic acid (1:0.5) pKa = 1.2, 4.2

TMZ·Acetic acid (1:1) pKa = 4.7

Half life of TMZ cocrystals by UV-Vis

N

NN

NN

CH3

ONH

2

O

NH2

N

O

NH2

NH

Water CO2

TMZ drugUV max at 330 nm

AIC, hydrolyzed TMZ UV max at 260 nm

CH3N2

DNA alkylation

Intrinsic dissolution rates in pH 7 buffer medium

Stability and Dissolution Criteria

TMZ oral form must be evaluated on stability and solubility criteria

Half life T½ of Temo at 10 M human plasma conc. = 1.8 h

T½ Temozolomide at pH 7 (pure water) = 1.7 h

Cocrystal with Anthranilic acid = 2.2 h, Succinic acid = 2.3 h, d,l-Tartaric

acid = 2.5 h, d,l-Malic acid = 2.7 h, Oxalic acid = 3.5 h, Salicylic acid = 3.6 h

Better physical form stability and equal/ faster dissolution rate to TMZ.

Long Term Stability of TMZ cocrystals

Cocrystal composition verified periodically by PXRD and IR

Physical stability and color comparison of pure TMZ (above) and

TMZ–SA cocrystal (below) under accelerated ICH conditions of 40 °C

and 75% RH. Whereas there is a darkening of color from pink/ light

tan to dark brown starting in the first week and up to 7 weeks, the

cocrystals is white in color for the entire duration. There was no

color change or decomposition (by PXRD) of TMZ–SA cocrystal up to

28 weeks at the same conditions.

0 W 1 W 3 W 7 W

Amorphous Drugs

Amorphous solids have high solubility, dissolution rate and sometimes

better compressibility than corresponding crystalline phase.

Because of the high thermodynamic properties they are highly metastable

physically and chemically than their corresponding crystalline counterpart.

Normally not preferred.

Can be prepared by standard pharmaceutical processes and are the

common forms of certain materials like proteins, peptides, some sugars and

polymers.

Condensation from the vapor state, Supercooling of the melt, Mechanical

activation of crystalline mass, for example during milling and cryo-milling and

rapid precipitation from solution, for example during freeze-drying or spray

drying are used to make amorphous material.

The amorphous material can be dispersed in a polymer matrix to enhance

its stability.

High Attrition Rates in Drug Discovery and Development

In contrast to the metastable nature of amorphous phases, cocrystals are

stable owing to their crystalline nature. Yet, cocrystals can exhibit dramatic

solubility advantage over the stable crystalline drug form, often comparable

to amorphous pharmaceuticals. The “spring and parachute” concept for

amorphous drug dissolution can explain solubility advantage of

pharmaceutical cocrystals

(1) the cocrystal dissociates to amorphous or nanocrystalline drug clusters

(the spring),

which (2) transform via fast dissolving metastable polymorphs to the

insoluble crystalline modification following Ostwald’s Law of Stages, to give

(3) high apparent solubility for cocrystals and optimal drug concentration (the

parachute) in aqueous medium

Plot 81 A/C, Unit D, MLA Colony, Banjara Hills, Hyderabad 500 034 director.crystalin@gmail.com, www.crystalin.org B. Mahalakshmi 98496 59109 Ashwini Nangia 98481 55416

Furosemide (Lasix)

Clotrimazole

Norfloxacin and Ciprofloxacin

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