Modulating Pharmaceutically Relevant

Properties of Drugs by Crystal Engineering

Dr. Palash Sanphui

Outlook
Why solid forms?
Several classifications of solid forms
Importance of polymorphsim
Pharmaceutical cocrystals and its applications
Pharmaceutical salts
Conclusions

Drug development and the present crisis

R & D funds not available

New drug approvals declining
Risk factors

What is Crystal Engineering?

It is the design of organic molecular
solids , their internal structure and
external morphologies
The understanding of intermolecular
interactions in the context of crystal
packing and in the utilization of such
understanding in the design of new
solids with desired physical and
chemical properties
It is an umbrella discipline, of various and
often uncorrelated areas, that is of the
greatest relevance to the pharmaceutical
sciences today

Specific solid forms of interest

A

A
A

A
A

A
A

A
A

A+
A+ A+
CCCCA+
C-

CA+

A+

A+
C-

A+

Salts

CA+

G
A

G
A
A

Cocrystals

Crystalline Molecular Complexes:

Co- Crystal / Salt Continuum

A
A
A
A

Polymorphs

Crystalline Molecular Complexes:

Analogous to Polymorph Solvate
(Except other Component in Crystal
Lattice is a6 Solid (not Liquid))

Polymorphism in Organic Crystals

A solid crystalline phase of a given compound
resulting from the possibility of at least two
crystalline arrangements of the molecules of
that compound in the solid state

Quartz crystal polymorphs

McCrone, W. C. Polymorphism. In Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.;
Weissberger A., Eds.; Wiley-Interscience: New York, 1965, Vol. 2, pp 725767
Desiraju, G. R. Nature Mater,1, 71, 2002

ICH Decision Trees

Polymorph Q1

Can different polymorphs be formed?

If yes, characterize the forms and go to Question 2

Polymorph Q2

Do the forms have different properties?

If yes, is product safety, performance, or efficacy affected?

If yes, set acceptance criteria for polymorph content in drug substance

and go to Question 3
Polymorph Q3
Does drug product performance testing provide adequate control if polymorph
ratio changes (e.g. dissolution)?
If not, monitor polymorph form during stability of drug product
Does a change occur which could affect safety or efficacy?
If yes, establish acceptance criteria consistent with safety and/or efficacy

Polymorphism and the Effect on

Bioavailability

Form I

Intestinal
Membrane

Form II

Dissolution/Solubility
Limited Oral Absorption
(e.g. chloramphenicol palmitate)

Intestinal
Membrane

Solubility: Form II > Form I

Gastric Emptying or Permeation
Limited Oral
Absorption
9
(e.g. ranitidine HCl)

Polymorphism and the Effect on

Manufacturability
Paracetamol Form I

Paracetamol Form II
Direct Compression

Wet Granulation

Paracetamol Form I
Joiris et al Pharm. Res. 15, 1122, 1998

Paracetamol Form II
10

Why refrigerated chocolate tastes better ?

Chocolate bloom is a whitish
coating that can appear on the
surface of chocolate.
Two types of bloom: fat bloom,
arising from changes in the fat in
the chocolate; and sugar bloom,
formed by the action of moisture
on the sugar ingredients.

S. T. Beckett, The Science of Chocolate,

Royal Society of Chemistry, London 2000.

Form V is commercialized (good taste)

11

Ritonavir. A Disappearing Polymorph?

Form I (Anti amide)

Form II (Syn amide)

Abbott laboratory $ 250 million loss!!!

There are 3 more crystalline forms of ritonavir.

Bauer, J. et al. Pharm. Res.,18, 859, 2001

Recent examples of API polymorphs

Sulfathiazole

Pentobarbital

Paracetamol

Fluconazole

Barbital

Metaxalone

Theophylline

Perindopril Erbumin

Indomethacin

Gabapentin

Aripiprazole

Ranitidine Hydrochloride

Huperzine A

Paracetamol

Irbesartan

Acemetacin

Nalidixic Acid

Felodipine

Pridopidine Hydrochloride

Etoricoxib

Oxalyl Dihydrazide

Menthol

Haloprogin

Sofosbuvir

Source: Articles in CGD and CEC in 2012-14

Solid forms of the anti-HIV drug Efavirenz

A: Thermodynamic;
B and C: Kinetic
Can we get new polymorph
comprises synthon B?

Form I

Form II

Ravikumar, K. et al. Mol. Cryst. Liq. Cryst., 515, 190, 2009

Mahapatra, S. et al., Cryst. Growth Des., 10, 3191, 2010

Tautomeric polymorphs
Omeprazole

Triclabendazole

5'-methoxy tautomer in form V

Bhatt, P. M. et. al, Chem. Commun., 2057, 2007

Form I

Form II

Tothadi, S. et al., Chem. Asian J., 7, 330,

2012

Polymorphs by desolvation??
To treat sleep disorder

Tg=67 C

Mahieux, J. et al. Cryst Growth Des. 16, 396, 2016

Polyamorphous API??
Valsartan (VAL) is an antihypertensive drug marketed as an amorphous form

Commercial

SSNMR
New form

AM contains equal ratio of cistrans conformers about the amide bond, whereas the
AR form exists mainly as one conformer, with minor conformational defects.
Skotnicki et al. Mol. Pharmaceutics, 13, 211222, 2016

Role of polymorphism during journey of a molecule from discovery to marketing

The issue of sameness for generic products

Approval of ANDA is based on therapeutic equivalence and bioequivalence.
Inventor has to confirm consistency in stability through the shelf life of the API.
Warfarin, famotidine, ranitidine, ritonavir, ampicillin, cefadoxin generic forms approved .
In case, solid form having physicochemical advantages and enhanced bioequivalence, these drugs
can be commercialized via NDA route.
In case innovator has patents on particular polymorph, successful paragraph IV filing provides
exclusive marketing rights for generic for 180 days and a healthy market share with innovator.

Few case studies (LRP)

Apremilast
(Inhibitor of phosphodiesterase)

Prior art:
Three anhydrous forms A, B and F and DCM, toluene, CH3CN and EtOAc solvates
reported
Amorphous form obtained from melt improved solubility.

Objectives
New polymorph with stability and reproducibility
Can we get a hydrate form? Donor acceptor imbalance??
Materials obtained from China was different from prior art. What is the procedure?
Class C

New crystalline forms of apremilast

PXRD (2/)

DSC/TGA/moist
ure content

Form B
(PLS/031
batch)
Outsource
(China)
Form C
In house (Form
L)
(PLS/033
batch)
In house (Form
M) hydrate(PLS/041
batch)

5.99, 7.83, 10.08,

13.44.

154.2-157.6 C
(Literature)

10.65, 11.20,
13.14, 14.69

144.90-149.88
C
0.132%
144.7-148.7 C
0.651%

New form
(anhydrous
form--PLS/047

7.90, 10.09,
14.64, 14.9,
17.23, 18.18,

8.39, 11.16,
13.11, 14.66

5.34, 7.38, 8.40,

13.96, 16.62.

39.29-55.20,
93.65-103.64,
143.44-146.54
C
3.00%
3.28%
155.98-157.72C
Wt. Loss: 0.33%

Class C

FT-IR

3447,
1765,
1618,
3357,
1696,

3363,
1706,
1597
1763,
1621

Methods
of
preparati
on
Acetone

THF-water

3443, 3356,
1763, 1697,
1621, 1595

DMFwater

3582, 3457,
3344, 1768,
1704,1648.4,
1594

DMFwater
(Reverse
addition)

3451, 3372,
3338, 1771,
1698, 1619

CHCl3cylcohexa
ne

Conclusions
Several new stable anhydrous forms and a monohydrate were obtained during
polymorph screening.
Monohydrate form was found to be quite stable and exhibited several batches in
Plant.

Class C

Tedizolid phosphate
To treat bacterial skin
and skin infections

Prior art:
Two crystalline anhydrous forms A, B are reported
Stable form A having 96% purity (remaining 4% organic impurities)

Objective
To obtain an amorphous form.
Observations
Solubility problems in organic solvents!!!
Only soluble in pH >7 buffer medium and DMF-water (3:1) at 95 C.
Class C

New solid forms of tedizolid phosphate

Sr. no.

Experimental details

Results

Crystallize from DMSO-water (1:3) by heat cool method

Form A

2.

Crystallize from DMF-water (3:1) by heat cool method

3.

Crystallize from DMSO-water (3:1) by heat cool method

Form A

4.

Crystallize from DMSO, followed by addition to excess water

Form A

5.

Crystallize from DMSO, followed by addition to excess water

Form A

6.

Crystallize using NaOH-formic acid treatment

Form A

7.

Crystallize from DMF-water (3:1) by rapid cool method

Form A

8.

Crystallize from aqueous ammonia via heating ammonia off

9.

Crystallize from aqueous ammonia via fast distillation

New crystalline form C

New crystalline form D

Amorphous NH4+ salt

10.

Crystallize from aqueous triethylamine via fast distillation

New dibasic salt

11.

Crystallize from aqueous triethylamine via fast distillation

New monobasic salt

12.

Slurry of monobasic NEt3 salt in water, followed by drying

monobasic salt

13.

Neutralization of monobasic NEt3 salt by phosphoric acid

Form A

14

Lyophilization of tedizolid phosphate using aqueous NH 3

15

Lyophilization of tedizolid phosphate using pH 7 buffer

16

Recrystallize of phosphate using pH 7 and excess MeOH

Semi crystalline form

Amorphous form
New crystalline form F

Three new crystalline forms, one semi-crystalline and one amorphous form obtained

Class C

Conclusions
Three new crystalline form of tedizolid phosphate obtained during solid
form screening. Crystalline forms are stable at ambient conditions.
One semi crystalline form and one amorphous form also obtained, but
they transformed to one of the crystalline form after 2 months at RT.

Class C

Controlled crystallizations
Crystal16

(16 exp. at a time)

High throughput
crystallizations
(96 plates)

EasyMax 402

Crystal Engineering and Supramolecular Synthons

Crystal engineering: The understanding of intermolecular interactions in the context of crystal
packing and the utilization of such understanding in the design of new solids with desired physical
and chemical properties.
Supramolecular synthons: Structural units within supermolecules which can be formed and/or
assembled by known or conceivable synthetic operations involving intermolecular interactions.
O H O

Homosynthons

O H N

S
O H O
acid-acid

S
N H O O

N H O
H

Heterosynthons

O H N

amide-amide

sulfonamide-sulfonamide

O H O

N H N

N H O

amide-pyridine

amide-acid

O H N
H
acid-pyridine

Pattern recognition is one of the key elements in crystal engineering strategy.

Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Elsevier: Amsterdam, 1989
Desiraju, G. R. et al. Angew. Chem. Int. Ed. Engl., 34, 2311, 1995
Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering: A Textbook; World Scientific: Singapore,

Cocrystals
Co-crystals: Solids that are crystalline materials composed of two or more
molecules in the same crystal lattice (FDA, December 2013)

Cocrystals are solids that are crystalline single phase materials composed
of two or more different molecular and/or ionic compounds generally in a
stoichiometric ratio, which are neither solvates nor simple salts.

Pharmaceutical cocrystals: are they the next big thing?

US FDA guidelines (December 2013)
If the API and its excipient(s) have a pKa < 1, there will be less than substantial proton
transfer. If this criterion is met, the active ingredient-excipient complex should be classified
as a co-crystal.
If, however, you believe that the classification of the pharmaceutical solid as a salt or cocrystal is not predicated on these relative pKa values, then spectroscopic tools using
various orthogonal approaches should be used to prove otherwise.
Assurance that complete dissociation of the API from its excipient occurs prior to
reaching the site of action for pharmacological activity.

EMA guidelines December 2014

Cocrystals, hydrates and solvates are held together by weak interactions that are in
most cases broken upon dissolution, similar to salts. When a drug substance in such
different forms is dissolved in the stomach or the intestinal canal, the likelihood is very high
that these different forms will expose the patient to the same active moiety.
Cocrystals, hydrates and solvates will therefore be considered eligible for generic
applications in the same way as salts are.

Potential Utility of Co-Crystals

API

API

No Ionizable Groups

Probable Molecular
: Patterns
Recognition
(e.g. H-bonding Rules)
with Guest Compound
Co-Crystal Solid State Engineering

Salt Form: Enhanced

Pharmaceutical Properties

Improved API Cocrystal

Solid State Properties
29

Crystal engineering and physicochemical properties

Solubility

Mechanical
properties

Tabletability

Crystal
engineering
and modulation of
properties

Permeability

Bioavailability

Physical and chemical stability

Drug development in R & D

Various stages of pharmaceutical cocrystals during drug development

Dugguria et al. Chemcomm. 52, 640, 2016

Bottlenecks in drug discovery

Permeability

Biopharmaceutical classification system

(BCS)
Class II

Class I

Low solubility
High permeability

High solubility
High permeability

Class IV

Class III

Low solubility
Low permeability

High solubility
Low permeability

Solubility

BCS Class Solubility

I
II
III
IV

high
low
high
low

1. Drug absorption in GI tract is controlled by

membrane permeability and
solubility/dissolution rate.
2. A drug is highly permeable when 90% is
absorbed.
3. A drug is highly soluble if highest dose
strength is soluble in 250 ml water .

Permeability % drugs
on market
high
35
high
30
low
25
low
10

% drugs in R &
D pipeline
5-10
60-70
5-10
10-20

Thayer, A. et. al. Chem. Eng. News, 88, 13, 2010

Cocrystals to clear bottlenecks?

* Do pharmaceutical co-crystals represent a new path to improved medicines?

Almarsson, . et al. Chem.Commun., 1889, 2004
* The role of cocrystals in pharmaceutical science
Shan, N. et al. Drug Discovery today, 13, 440, 2008
* Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals
Babu, N. J. et al. Cryst. Growth Des., 11, 2662, 2011
* Cocrystallization for successful drug delivery (review)
Sun, C. C. et al. Expert Opin. Drug Deliv., 10, 201, 2013

* Pharmaceutical cocrystals: along the path to improved medicines

Duggirala, N. K. et al. Chem.Commun., 52, 640, 2016
Choose a solid form with modulated properties during development stage.

Solubility and cocrystals

Fluoxetine hydrochloride (brand
name-Prozac) is marketed as an
antidepressant.

Fluoxetine hydrochloride
cocrystals improve solubility
Childs et. al. J. Am. Chem. Soc., 126, 1335, 2004

Itraconazole (Sporanox) marketed as an

antifungal as a solid dispersion with amorphous
HPMC polymer.

Itraconazole cocrystals are as soluble

as marketed amorphous phase
Remenar et. al. J. Am. Chem. Soc., 125, 8456, 2003

Decreased solubility and Improved pharmacokinetics

Epigallocatechin gallate, the most abundant catechin in tea.

Poor bioavailability even after at such a high amount of daily intake (8-16 cups of tea
(800 mg).

Epigallocatechin gallate
(Solubility 50 g/L)

Reducing solubility reduces

dissolution rate and delays the
time at which maximal plasma
levels are reached (Tmax).
EGCgNIC9H2O had the most
rapid Tmax after free EGCg.
Smith et al. Mol Pharmaceutics 10, 2948, 2013

Pharmacokinetics data

100 mg dose
of EGCG per kg
body weight in rats

Smith et al. Mol Pharmaceutics 10, 2948, 2013

Bioavailability and cocrystals

2-[4-(4-chloro-2-fluorophenoxy)
phenyl]pyrimidine-4-carboxamide
-glutaric acid cocrystal

Carbamazepine-saccharin cocrystal

McNamara, D. P. et al. Pharm. Res., 23, 1888, 2006 Hickey, M. B. et al. Eur. J. Pharm. Biopharm., 67, 112,
2007

Permeability and cocrystals

Dissolution

Maleate salt, 1

Acyclovir
Permeability
Fumaric acid cocrystal dihydrate, 2

Glutaric acid cocrystal, 3

Glutaric acid cocrystals improve permeability of acyclovir

Yan, Y. et al. CrystEngComm, 15, 6457, 2013

Tableting properties and cocrystals

Paracetamol Form I (Stable Form)
Crystal Lattice Compact
Corrugated Layers
Difficult to Compress

Cocrystals
improved
tabletting
properties

Karki S. et al. Adv. Mater., 21, 3905, 2009

Paracetamol-trimethylglycine cocrystal: improved tablettibility and taste

ACM

TMG

TMG >>food sweetener and dietary supplement.

Dissolution
ACM-TMG
ACM-OXA
ACM

ACM-TMG

ACM-OXA

Both the cocrystals showed similar compression and dissolution properties .

ACM-TMG is superior than ACM-OXA because TMG suppress the bitterness of ACM.
Fukami et al Int J Pharm 473, 179-186, 2014

Chemical stability and Cocrystals

Temozolomide-Succinic Acid

0w

1w

3w

7w

TMZ started decomposing in ACC RH after 1w.

TMZ-SA cocrystals were stable up to 6 months.
Cocrystals showed similar dissolution rate as
the API.

Babu, N. J. et al. Chem. Asian J., 7, 2274, 2012

Drug-drug cocrystals
Anti-HIV Drugs Lamivudine and Zidovudine
Lamivudine was approved by the FDA in
1995 in combination with Zidovudine

Lamivudine

Zidovudine

Lamivudine-zidovudine cocrystal hydrate

Bhatt, P. M. et al. Cryst. Growth Des., 9, 951, 2009

Pharmacocrystals: Along the path to improved medicines

Metaxalone-fumaric acid cocrystals showed improved PK study in beagle dogs and is under
clinical trials.
Danazole-vanilin cocrystals improved solubility and absorption in presence of 1% TPGS and
2% HPC.
Novel formulation of Tramadol HCl with celecoxib (Adolonta) achieved higher plasma
concentration compared to individual drugs.
Valproic acid (Depakene) is liquid at RT, but sodium divalproate (Depakote) is solid and
shows comparable PK behaviour. It is the leading marketed form of valproic acid.
Diabetes drug Ertugliflozin cocrystal with L-pyroglutamic acid is under phase III clinical
trials, lead by Pfizer and Merck.

Ertugliflozi

L-pyroglutamic acid

Dugguria et al. Chemcomm. 52, 640, 2016

(1:1) Cocrystal

An approved pharmaceutical ionic cocrystal

Novartis gained approval for EntrestoTM to treat chronic heart failure in July 2015.
Composed of monosodium sacubitril, disodium valsartan and water.
A significant mortality benefit and patient tolerance.
Pending further approval form regulatory approvals.
EntrestoTM (Sacubitril-Valsartan tri-sodium 2.5 hydrate) has potential market value of
several billion USD.

Chemical compositions of cocrystals

Drawbacks of cocrystals
Toxicosis Caused by Melamine and Cyanuric Acid in Dogs and Cats

FDA permits a certain amount of cyanuric acid to be present in some nonprotein nitrogen (NPN) additives used in animal feed
Cyanuric acid is classified as "essentially nontoxic".
When cyanuric acid is present together with melamine (another low-toxicity
substance), they may form extremely insoluble cocrystals, leading to formation
of kidney stones and potentially causing kidney failure and death.

+
Cyanuric acid

Melamine

Melamine cyanurate

Soluble

Soluble

Insoluble

Puschner et el. Clin Lab Med 31, 181, 2011

Literature survey

(a) Published articles on co-crystals 19952014. (b) Citations for articles on

co-crystals 19952015

Aakery et al, Acta Cryst. B71, 387391, 2015

Literature update on cocrystals and patents

Classification of common pharmaceutical salts

Anions
Inorganic acids: hydrochloride, hydrobromide, sulfate, nitrate, phosphate, sulfonic acids
mesylate, esylate, isethionate, tosylate, napsylate, besylate
Carboxylic acids: acetate, propionate, malate, maleate, benzoate, salicylate, fumarate,
oxalate
Anionic amino acids: glutamate, aspartate
Hydroxyacids: Citrate, lactate, succinate, tartrate, glycollate, gallate
Fatty acids: hexanoate, octanoate, decanoate, oleate, stearate
Insoluble salts: pamoate (embonate), polystyrene sulfonate (resinate)
Sulfonic acid: Camphor sulfonate
Cations
Organic amines: triethylamine, ethanolamine, triethanolamine, meglumine,
ethylenediamine, choline
Insoluble salts: procaine, benzathine
Metallic: sodium, potassium, calcium, magnesium, zinc
Cationic amino acids: arginine, lysine, histidine

Bastin et al. Org. Pro. Res. & Dev. 4, 427-435, 2000

Salts and improved tableting properties

Perumala et al. CrystEngComm, 14, 2389, 2012

Salts and improved dissolution

Bolla et al. Cryst. Growth Des. 12, 6250, 2012

Salts and improved pharmacokinetics

Glutarate salt improved both IDR

and AUC properties compared to
marketed citrate salt

Sanphui, P. et al. Mol. Pharmaceutics 10, 4687, 2013

Salts and hydration stability

Sanphui, P. et al. IUCrJ, 1, 136, 2014.

Acemetacin-piperazine salt is stable during dissolution expt, whereas drug turned to hydrate.

Anti-microbial drug

Sweet Berberine
Acesulfame salt

Stable and pleasant

Bitter taste &

Hydration problem

Saccharin salt

Dissolution

Lower dissolution rate of salts with sweeteners achieved masking bitterness.

Wang, C et al. Cryst. Growth Des. 2016

Conclusions
High throughput screening must be used for polymorphs findings.
Controlling polymorph via crystallization is a great challenge in Kg scale.
Cocrystals can be prepared on the basis of supramolecular heterosynthons
and shape/size mimicry.
Drug drug cocrystals have the advantage of one tablet with better clinical
activities than the combination of drugs.
Pharmaceutical cocrystals have the diverse applicability compared to the
API salt and can promote BCS class II-IV drugs to I category.
Salts may exhibit better properties compared to cocrystals.
Joint efforts of chemical crystallographer, formulation chemist and material
chemist is urgently required for better therapies based on scientific research.
Both US-FDA and EMA issued guidelines for pharmaceutical cocrystals.
More numbers of cocrystals will be screened for clinical trials in near future.

INDInvestigational Drug Application

Why do we need cocrystals?

Solubility
Bioavailability
Dissolution rate
Tabletability
Chemical stability

2-[4-(4-chloro-2-fluorophenoxy)
phenyl]pyrimidine-4-carboxamide

Acid-amide heterosynthon

API

cocrystal

Cocrystal improves solubility by 18 times and bioavailability by 3 times than API.

McNamara, D. P. et al., Pharm. Res., 23, 1888, 2006

Why cocrystals dissolve faster than the API?

Spring and parachute model

Possible mechanism

Spring and parachute concept to achieve high apparent solubility of a poor soluble API
Generally high soluble coformer assist the API to gain higher solubility
Babu et al Cryst. Growth Des. 11, 26622679, 2011

Few recent techniques for controlling solid forms

Hot melt extrusion

Advantages
Continuous processing efficiencies (high throughput, low cost, no solvent/water)
Improved product uniformity
Enhanced solubility/bioavailability due to molecular dispersion of the solid.
Can be used to make granules for tableting.
Metformin HCl becomes easy to make tablets after hot melt extrusion technique

Melt granulation: application in continuous processing

Melt granulationa promising technology for poor soluble drugs

Agitated thin film dryer (ATFD) and Spray dryer

ATFD can evaporate water/solvents to make
concentrated liquid to dry powder of flakes.
Drying of products of drugs and its intermediates to
eliminate conventional process of drying
Suitable for thermally sensitive products as mainly
run in high vacuum.
To procure amorphous form or metastable form of a
drug in pharma industry.

Spray dryer produces a dry powder from a liquid or slurry

by rapidly drying with a hot gas.
It provides verities of particle sizes (1m to 1nm) depends
upon need.