Ongoing Projects Curcumin–Pyrogallol Polypill
Contact Information
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 [email protected], www.crystalin.org B. Mahalakshmi 98496 59109 Ashwini Nangia 98481 55416
Furosemide (Lasix)
Clotrimazole
Norfloxacin and Ciprofloxacin
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