Structure and polymorphism of solid pharmaceutical substances

Pharmaceutical cocrystals

Bohumil Kratochví[email protected]

Chemie a fyzika pevných léčiv 2019

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Content

Cocrystal, pharmaceutical cocrystal – definition

Pharmaceutical cocrystal proccesing

Why cocrystals are interesting for pharmacy

Cocrystal classification

Cocrystal desing

Cocrystal partners (active substances and coformers)

Cocrystal prediction

Cocrystal preparation strategy

Cocrystal analytics

Conclusion

Crystalline Multi-Component compounds

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The charming word "cocrystal" was first used at work:Hoogsteen K.: Crystal and Molecular Structure of a Hydrogen-BondedComplex Between 1-Methylthymine and 9-Methyladenine. Acta Crystallogr. 16, 907 (1963).

Crystalline Multi-Component compounds have very branchedterminology: … mixed crystals, clathrates, inclusion compounds, organic molecular compounds, molecular complexes, heteromolecularcrystals, supramolecular adducts… and cocrystals (co-crystals)

A co-crystal is not a mixture, but a new chemical entity !

The first prepared mixed crystal (cocrystal) was quinhydrone, studied by Friedrich Wöhler in 1844. Quinhydrone is a cocrystal of quinoneand hydroquinone (known archaically as quinol). He found that this material was made up of a 1:1 molar combination of the components.

Cocrystals

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Definition: cocrystals are solids that are crystalline single phase materials composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts

Cocrystal applications- Optical or photo-responsive materials (aminopyrazine with boric acid)- Medicine and energetics (nano-cocrystals)- Agrochemicals and pigments- API in pharmacy (pharmaceutical cocrystal)

A pharmaceutical cocrystal, definition: a stoichiometric multicomponent host-guest compound (host = active molecule, guest = cocrystallization former, coformer1) formed from two or more components that are solid in a pure state and at room temperature2. The host-guest stoichiometric ratio is mostly simple (1:1, 2:1, 3:1, 4:1, and 1:4, respectively). Eg. Carbamazepine : 4-aminobenzoic acid cocrystal system, can exist in 1:1, 2:1, and 4:1 stoichiometric configurations.

1. Even the coformer may be an active molecule, e.g. cocrystal theophylline:nicotinamide (1:1). 2. Aakeröy C.B., Salmon D.J.: CrystEngCommun. 7, 439 (2005).

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Pharmaceutical cocrystal – an example

Cocrystal carmabazepine: saccharin (1:1)

(carbamazepine forms with different coformers about 50 cocrystals)

Cocrystal carbamazepine : saccharine (1:1)

How cocrystals held together

- - -

Zaworotko M.: Crystal engineering of cocrystals and their relevance to pharmaceutical and solid state chemistry. IUCr2008, KN32. Osaka 2008.

H-bonds H-bonds H-bonds H-bonds

The molecules in co-crystals retain their covalent identity

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Cocrystal processing – a beginning of the story

1) Syntetic and crystallographic epoch, academics (1963 – 2000)

Hoogsteen K.: Cocrystal of 1-methylthimine and 9-methyladenine. Acta Crystallogr. 16, 907 (1963).

2) Study of cocrystal application in pharmacy, patents (2000 – today)

3) Regulatory Classification of Pharmaceutical Co-Crystals. Guidance for Industry (February 2018). U.S. Department of Health and Human Services Food and Drug

Administration Center for Drug Evaluation and Research (CDER) Pharmaceutical Quality/CMC.

Cocrystals were finally and oficially recognized by FDA in 2018, as a new broad class of APIs

Cocrystal patents

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Trend of co(−)crystals in WIPO patent database from 2004 until December 2017

Maryam Karimi-Jafari, Luis Padrela Gavin M. Walker, Denise M. Croker:Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and ApplicationsCrystal Growth & Design2018 18 (10), 6370-6387.

9http://www.mhra.gov.uk/spc-pil/?subsName=AGOMELATINE%20/%20CITRIC%20ACID%20CO-CRYSTAL&pageID=SecondLevel

Co-crystals in medical practice

Chemical and physical forms of solid APIs

So, pharmacy has hundreds of possible solid APIs (from onemolecule) available for drug formulation development

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Criteria of the optimal API choice for solid dosage form

Functional, technological, commercial and legal aspects

A patient uses no separated molecule, but solid state !

Terapeutical (biological) activitySolubility, dissolution rate,

permeability, bioavailability

Stability (chemical and physical)Robustness and reproducibility of

manufacture

Chemical and physical purity Resistance to mechanical stress

Hygroscopicity Processability

Choice of crystalline or amorphous

phasesDose amount

Tendency to polymorphism Taste acceptability

Compatibility with excipientsPossibility of corrosion of production devices

Toxicity Patent collision

J.BudkaJ.Budka

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Some well-known pharmaceutical cocrystals

Active molecule : coformer

carbamazepine : saccharine carbamazepine : nicotinamidepiroxicam : sodium acetateitraconazole : L-tartaric acid itraconazole : succinic acid norfloxacin : isonicotinamideibuprofen : nicotinamidetrospium chloride : ureacelecoxib : nicotinamideagomelatine : hydroquinonemelamine : cyanuric a.

Cocrystals are not pharmacodynamically more effective than pure (parent) active substance itself, but they modify (optimize) its technological or function parameters, eg. solubility, dissolution profile, oral bioavailability, physical and chemical stability, hygroscopicity, flow properties, mechanical properties, etc .

Active molecule : coformer

etravirine : nicotinamideparacetamol : theophylinequercetin : caffeinesildenafil : acetylsalicylic acidmirtazapin : dicarboxilic acidsmyricetin : 4,4′-bipyridinefurosemide : picolinamdeaspirin : 4,4′-bipyridine5-fluorouracil : ureaivabradine hydrochloride (S):mandelic acid

Why cocrystals are interesting for pharmacy –examples

Active substance Cocrystal Cocrystal parameters

ibuprofen ibuprofen : nicotinamide lower hygroscopicity

indomethacin indomethacin : saccharine better dissolution rate

norfloxacin norfloxacin : isonicotinamide

norfloxacin : succinic a. (or malonic a.)

better solubility,

better crystal shape

caffeine caffeine : malonic a. no hydrates are formed at

the high relative humidity

paracetamol paracetamol : theophyline (or

napthalene)

better tablet strength

carbamazepine carbamazepine : saccharin no polymorphs or

hydrates are formed

hydrochlorothiazide hydrochlorothiazide : sucralose taste masking

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Why cocrystals are interesting for pharmacy ?

Amorphous itraconazole (API) Sporanox® (Salutas Pharma), antifungal drug

The first case study – modification of the dissolutin profile

Cocrystals of itraconazole with 1,4-dicarboxylic acids:

L-malic, L-tartaric and succinic

Example: cocrystal of itraconazole with succinic acid (2:1)

„sandwich structure“

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Cocrystals can modify dissolution profile

Morissete S.L. et al.: Advaced Drug Delivery Reviews 56, 275 (2004).

itraconazole amorphatecocrystal itraconazole : L- malic acid (2:1)

cocrystal itraconazole : L- tartaric acid (2:1)cocrystal itraconazole : succinic acid (2:1)

itraconazole crystalline

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PICO – picolinic a.NICO – nicotinamideCAFF – caffeine

Chadha, K.; Karan, M.; Bhalla, Y.; Chadha, R.; Khullar, S.; Mandal, S.; Vasisht, K. Cocrystals of Hesperetin: Structural, Pharmacokinetic, and Pharmacodynamic Evaluation. Cryst. Growth Des. 2017, 17 (5), 2386–2405.

Cocrystallization of trospium chloride with urea

Trospium chloride –urinary antispasmodic

Urea

Cocrystal trospium chloride : urea (1:1)

Crystal structure of cocrystal 16

Cocrystallization of trospium chloride with urea

1. Skořepová, E., Čejka, J., Hušák, Eigner, V., Rohlíček, J., Šturc, A., Kratochvíl, B.: TrospiumChloride: Unusual Example of Polymorphism Based on Structure Disorder. Cryst. Growth Des. 13, 5193–5203 (2013).

2. Sládková V., Cibulková J., Eigner V., Šturc A., Rohlíček J., Kratochvíl B.: Application and Comparison ofCocrystallization Techniques on Trospium Chloride Cocrystals. Cryst. Growth Des. In print (2014).

3. Skořepová E., Hušák M., Čejka J., Zámostný P., Kratochvíl B.: Increasing dissolution of trospium chloride by co-

crystallization with urea. J. Cryst. Growth 399, 19-26 (2014).

Modification of the dissolution profile

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Trospium chloride


The second case study – bypassing the problem of polymorphism

N

NH2O

Carbamazepine (crystalline API), dosage form Tegretol®,(Novartis), anticonvulsant

Carbamazepine has bad properties:

polymorphic molecule – 4 polymorphs are described

forms several solvates and hydrates

bad dissolution profile

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Cocrystal of carbamazepin : saccharin (1:1) solves a polymorphism problem

N

NH2O

NHS

O

OO

Crystal structure of one carbamazepine polymorphs

Crystal structure of cocrystal carbamazepine : saccharine (1:1)

:

This cocrystal is monomorphic and no its solvates or hydrates are known

Fleischman G.S. et al.: Crystal Growth & Design. 3, 909–919 (2003).19

The third case study – the separating cocrystallization

Samas B. et al.: Acta Crystallogr. E63, 3938 (2007).

pregabalin (API)

dosage form Lyrica®,(Pfizer),

anticolvulsant

Crystal structure of the cocrystal

(S)-pregabalin : (S)-mandelic a. (1:1)

Cocrystallization of pregabalin with (S)-mandelic acid separates only (S)-pregabalin from racemic mixture


(S)-pregabalin

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The forth case study – improving of mechanical properties


Paracetamol (analgesic and antipyretic API)

Polymorph I – stable for dosage formulation

Polymorph II - unstable Polymorph III - unstable

Jones W.: 25.European Crystallographic Meeting. Istanbul 2009.

paracetamolpolymorph I

paracetamol:theophyline (1:1)

paracetamol:napthalene (2:1)

paracetamol:oxalic a. (1:1)

paracetamol:phenantroline (1:2)

Paracetamol cocrystals have better tablet strength than pure paracetamol polymorph I

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Cocrystal classification (nomenclature)

Cocrystals (binary, ternary, quarternary …) Cocrystals solvated (hydrated) Cocrystals of salts (ionic cocrystals) Cocrystals of salts solvated (hydrated) Cocrystal polymorphism (packing and conformational)

ko, ko, ko ….22

Binary and higher cocrystals

Binary cocrystal

Quarternary cocrystal

Ternary cocrystal

Bhogala B.R. et al.: New J. Chem. 32, 800 (2008).

H3CTA

bipy H3CTA

H3CTAH3CTA

H3CTA

bipy

H3CTAH3CTA

H3CTA

H3CTAbipy-etabipy-Brete

bipy-diBreta

bipy-eta

H3CTA – cyklohexantricarboxylic a.bipy - bipyridine

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Cocrystal solvated

Solvated cocrystal - cocrystal contains a component that isliquid at room temperature

Cocrystal norfloxacin : isonicotinamide : chlorophorm (1:1:1)

isonicotinamidenorfloxacin (antibacterial agent)

chlorophorm

H-bond

Basavoju S., Boström D., Velaga S.P.: Crystal Growth & Design 6, 2699-2708 (2006).24

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Cocrystal hydrated

theophylline citric acid

water

Cocrystal theophylline : citric acid : water (1:1:1)

Lange L., Sadowski G.: Crystal Growth & Design 16, 4439-4449 (2016).

When free acids, free bases or neutral molecules have available

free H-donors or H-acceptors form stable hydrates

Why form molecules hydrates ?

dipicolinic acid proton acceptor available

proton acceptor available

proton acceptor available

Anhydrate (unstable)

Hydrate is more stable (all H-donors and H-acceptors are involved in H-bonding)

All good proton donors and acceptors are used in hydrogen bonding (Etter‘s rule)

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Hydrate (stable)

Ionic cocrystals (cocrystals of salts)

fluoxetine hydrochloride (antidepresivum), Prozac® (Eli Lilly)

fluoxetine hydrochloride : benzoic acid (1:1)

fluoxetin hydrochloride : succinic acid (2:1) fluoxetine hydrochloride : fumaric acid (2:1)

Childs S.L. et al.: J. Amer. Chem. Soc. 126, 13335 (2004).

Host is the pharmaceutical salt – fluoxetine hydrochloride

ionic cocrystals

ionic cocrystals ionic cocrystals

salt

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caffeine

N

NN

N

O

O OH O

OHO

glutaric acid

+

Cocrystal caffeine : glutaric a. (1:1)

Trask A.V. et al.: Chem. Commun. 2004, 890.

cyclohexane chlorophorm

Cocrystal conformational polymorphism

polymorf I

polymorf II

„”Every compound has different polymorphic forms and that, in general, the number of forms known for a given compound is proportional to the time & energy spent in research on that compound”

Walter McCrone, 1963

Dropping solvent

polymorf I polymorf II

Conformational polymorphism

(liquid-assisted grinding)

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Cocrystal packing polymorphism

Two polymorphs of cocrystal caffeine (blue) : theophyline (green)

Two polymorphs of cocrystal urea (green) : 4, 4‘ - bipyridine (blue)

Salts vs. cocrystals - where is the border between them

Cocrystal dihydrogenphosphate of „active molecule“ : phosphoric acid (1:1)

proton stays on the acid: H3PO4proton moves to nitrogen: H2PO4

–

Crystallization of „active molecule“ withtwo molecules of phosphoric acid – twodifferent bond situations

Chen M.A. et al.: Chem. Commun. (2007) 419.

O1 O2

Different character of two phosphoric acid molecules in cocrystal

„active molecule“

phosphoric a.

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Boundary line between cocrystal and salt

The reaction between carboxylic acid and basic heterocycleExample: benzoic acid + 3,5-dichlorpyridine ?

3,5-dichlorpyridinium benzoate or ? cocrystal 3,5-dichlorpyridine : benzoic a. (1:1)

Salt (yes, proton transfer) Cocrystal (no proton transfer)

Direct determination of H-position: high-quality of X-ray single crystal data, NMR, neutron diffraction, photoelectron spectroscopy (XPS), Undirect determination of H-atom position: X-ray diffraction (from bond lenghts C-O and angles O-C-O)

Position of hydrogen atom (proton resp.) determines if salt or cocrystal is formed

1Å1Å

1,5 Å1,5 Å

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Skořepová et al., Acta Crystallographica A 2014, A70, C1024.

agomelatin benzensulfonate (1:1)

Methods for determination of H-atom position

a) High-quality of X-ray single crystal data

Salt: C-O(longer) – C-O(shorter) < 0,03Å ; C-O(longer)/C-O(shorter) =1,027(15) ; C-N-C > 120o

Cocrystal: C-O(longer) – C-O(shorter) > 0,08 Å ; C-O(longer)/C-O(shorter) =1,081(12) ; C-N-C = 117,7-118,5o

b) Undirect determination of H-atom position: X-ray diffraction (from bond lenghts C-O and angles O-C-O)

zolpidem base

zolpidem cation

tartrate anion

bis-methanol

solvate

Čejka J., Jegorov A., Kratochvíl B. : Internal report, Teva (2007).

Ionic cocrystal – example from Teva

cocrystal zolpidem hydrogentartrate : zolpidem base bis-methanol solvate (1:1:2)

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15N ssNMR spektra různých pevných forem agomelatinu

Korelace mezi SXRD a 15N ssNMR výsledky v rozlišení solí a kokrystalů.

Resolution of salts and co-crystals by ssNMR method for agomelatin

sůl (k. benzensulfonová)

kokrystal

(k. citronová.)

polymorf I

polymorf II

sůl (k. sírová)

sůl (k. fosforečná)

sůl (k. methansulfonová)

sůl (k. chlorovodíková)

sůl (k. bromovodíková)

Kokrystaly

Soli

Převzato z dizertační prezentace ing. E. Skořepové, PhD. (2016)

If X-ray single crystal data are not available, the ssNMR

method can yield a reliable estimate

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How cocrystals are held tohether – cocrystal design

Chemical bonds between host (active molecule) and guest (coformer) in cocrystals are mostly H-bonds, Host-guest adducts are connected mostly via - interactions or VdW forces).

Theory of supramolecular synthons of the host-guest bond

Homosynthon Heterosynthoncarboxyl---carboxyl carboxyl---pyridine

A cocrystal is essentially a molecular crystal that breaks down (dissolves) into its covalent components (active molecule + coformer) in the digestive tract

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Homo- and heterosynthon types

Furcated H-bonds

More than 120 different homo- and heterosynthons are described in Cambridge Structural Database*. Heterosynthons are energetic better ones, but result of competition of number of synthons during cocrystal forming is difficult to predict

* The Cambridge Structural Database (CSD)https://www.ccdc.cam.ac.uk/solutions/csd-system/components/csd/

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Homosynthons (a,b), heterosynthons (c,d,e)

https://www.ccdc.cam.ac.uk/solutions/csd-system/components/csd/

π-π Interaction as intermolecular bond in cocrystals

Common interaction in molecular crystals with aromatic systems

Examples of the

face–to-face

π-π interaction 37

cocrystallization or recrystallization ?

The synthesis of new cocrystals is affected by many variables, which are mostly affected by the nature of solvent and the reactants. the stoichiometric ratio of the coformer and API, temperature, stirring, pH, and type of glassware are just a few of the effective parameters. On the other hand, the rules of hydrogen bonding, synthons, and graph sets could be helpful in designing cocrystal systems. However, there is no guarantee for cocrystal formation. Thus, preparation of cocrystals is often a multistage and empiric process.Unfortunately, we do not know all details of the co-crystallization process and the all details of the chemical bonds in cocrystals !

Cocrystal prediction

38Maryam Karimi-Jafari, Luis Padrela, Gavin M. Walker, Denise M. Croker:Crystal Growth & Design 18(10), 6370-6387 (2018).

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How to estimate the co-crystallization potential of various active molecules?

Trospium chloride

(spasmolyticum)

Alaptide

(dermatologicum)

Agomelatin

(antidepresivum)

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How to estimate the co-crystallization potential of various active molecules?

Trospium chloride Alaptide Agomelatin

10 cocrystals prepared No cocrystal 3 cocrystal prepared

Unfortunately, the co-crystallization potential of the active molecule cannot be predicted in advance

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Piroxicam (an anti-inflammatory substance)

3 polymorphs, 1 hydrate, 3 solvates, about 50 cocrystals,

7 polymorphs, about 50 cocrystals, amorphous phase

Indomethacin (a nonsteroidal anti-inflammatory substance)

Some active molecules form about 50 cocrystals

About 50 cocrystallization partners (caboxylic acids, amides or alcohols as coformers) are approved as safe for pharmacy (GRAS)

Vliv různých efektů na výsledek kokrystalizace

N

NN

N

O

O

Friščic' T.: Mechanochemical approaches for the construction and discovery of API cocrystals. 24. EuropeanCrystallographic Meeting. Marrakech 2007.

Efekt methylové skupiny výchozí aktivní molekuly na uspořádání kokrystalu

theofylin

nebo +

pKa= 2,5pKa= 3,6

N

NN

NH

O

O

Kokrystal theofylin : k.šťavelová (2:1)nekonečný řetězec

kofein

Kokrystal kofein : k.šťavelová (2:1)izolovaný útvar

k. šťavelová

pKa= 8,8

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Cocrystallization formers (coformers)

1. Carboxylic acids:

adipic a., benzoic a., fumaric a., salicylic a., malonic a., adipic a., glutaric a., caprylic a. citric a., succinic a. etc.

2. Amides:

nicotinamide, isonicotinamide, urea, saccharine, etc.

3. Alcoholes:

manitole, sorbitole, xylitole, etc.

See FDA directives: GRAS (Generally Recognized as Safe) and US EAFUS ("Everything" Added to Food in the United States).

About 50 cocrystallization partners is approved as safe for pharmacy

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Predikční výběr koformerůZvolený přístup: Tvar a polarita

• Statistické hodnocení existujících

kokrystalůa

– Cambridgeská strukturní databáze

– cca. 1000 struktur

• „Podobné s podobným“

– Korelace nalezena pouze pro některé

parametry

– Polarita, tvar

• Testováno v roce 2012b

– Synthonový přístup:

• Testováno 218 koformerů,

nalezeno 48 kokrystalů

– Komplementární přístup:

• Počet experimentů snížen o 50%

• Úspěšnost zvýšena z 22% na

37%

Distribuce polarit molekulárních

párů v existujících kokrystalech

Určení molekulárních tvarových parametrů L

MS

Míra úspěšnosti nalezení

kokrystalů

a Fabian, L., Cryst Growth. Des, 2009, 9, 1446-1463.b Fabian, et al., Pharmaceutical salts and co-crystals, 2012, 89-109

Převzato z dizertační prezentace ing. E. Skořepové, PhD. (2016)44

Predikční výběr koformerůPraktické provedení

Finální pořadí

Koformer

Farmaceut.

přijatelnost

Výpočet ΔpKAKyselina/

Báze/

NeutrálníΔpKA

Polarita

CCFs Velikost

CCFs

Rozdíl v

polaritě

Tvarové

parametry

CCFs

Rozdíl ve

tvaru

Nalezené

kokrystaly

CCF skóre

CCF skóre

s vlivem

farm. přij.

pKA (API)

Polarita

API

Velikost API

Tvarové

parametry

API

Převzato z dizertační prezentace ing. E. Skořepové, PhD. 45

Δ pKA = pKA(base) - pKA(acid)

Δ pKA = -0,94 - (-7,0) = 6,06Agomelatin + HCl

Δ pKA = -0,94 - (13,9) = -14,84Agomelatin + Urea

Cocrystal

Salt

Δ pKA = -0,94 - (-1,1) = 0,16Agomelatin + Benzensulf. a.

??? = continuum salt…cocrystal

(H-atom is situated strictly between O and N atoms,

so it is shared)

1,25 Å 1,25 Å

O – H – N

An empirical prediction: Δ pKA rule

vzorek ΔpKa SXRD Sůl/KK ss-NMR Sůl/KK

agomelatin-isonikotinamid -15,34 Ano2 KK Ano KK

agomelatin-ethylen glykol -14,97 Ano1 KK Ne

agomelatin-močovina -14,84 Ano2 KK Ne

agomelatin-hydrochinon -11,14 Ano KK Ano KK

agomelatin-methyl-4-hydroxybenzoát -9,12 Ano2 KK Ne

agomelatin-kys. octová -5,63 Ano1 KK Ne

agomelatin-kys. 4-hydroxybenzoová -5,41 Ano KK Ano KK

agomelatin-kys. gallová -5,17 Ne Ne

agomelatin-kys. glutarová -5,17 Ne Ne

agomelatin-kys. glykolová -4,31 Ano2 KK Ne

agomelatin-kys. gensitová -3,85 Ne Ne

agomelatin-kys. citronová -3,59 Ano KK Ano KK

agomelatin-kys. malonová -3,54 Ne Ne

agomelatin-kys. maleinová -3,08 Ano KK Ne

agomelatin-kys. fosforečná -2,90 Ano Sůl Ano Sůl

agomelatin-kys. ketoglutarová -2,78 Ne Ne

agomelatin-kys. šťavelová -1,78 Ano KK Ano KK

agomelatin-kys. benzensulfonová 0,16 Ano Sůl Ano Sůl

agomelatin-kys. methansulfonová 1,48 Ano Sůl Ano Sůl

agomelatin-kys. methansulfonová (hyd.) 1,48 Ano Sůl Ne

agomelatin-kys. p-toulensulfonová 2,36 Ne Ne

agomelatin-kys. sírová 2,56 Ano Sůl Ano Sůl

agomelatin-kys. chlorovodíková 6,06 Ne Ano Sůl

agomelatin-kys.bromovodíková 7,06 Ano Sůl Ano Sůl

agomelatin-kyselina jodovodíková (2:3) 9,36 Ano Sůl Ano Sůl

agomelatin-kys.jodovodíková (1:2) 9,36 Ano Sůl Ano Sůl

agomelatin-kys. jodovodíková (1:1) 9,36 Ano Sůl Ano Sůl

Zheng S.-L., et al. Crystal Growth & Design 11, 466-471 (2011).Yan, Y., et al. Crystal Growth & Design 12, 2226–2233 (2012).

Childs S.L et al.: J. Amer. Chem. Soc. 126, 13335 (2004).

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Preparation of cocrystals - classical cocrystallization techniques

Spontaneous cocrystallization

Solution evaporation (with solvent)

Solid-state co-grinding (without solvent orwith solvent)

Co-sublimation (without solvent)

Co-melting (without solvent)

Co-heating (without solvent)

Unfortunately, almost all cocrystals which could be prepared by simple classical techniques are already described. The universal cocrystallization strategy does not exist ! 47

?

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The application of the η-parameter to predicte cocrystallization methodologies

Friščic T, Childs SL, Rizvi SAA, Jones W.: CrystEngComm 11(3):418-426 (2009).

On the basis of the parameter η we can classify those methods, from neat grinding, where

η is equal to zero, through liquid-assisted grinding (η = 0.2-12 mg ml-1), suspensions (η = 2

to 12 mg ml-1) to cocrystallizations from solutions (η >> 0). By this approach, the methods

differ mainly in the amount of solvent and the saturation ratio of the input substances.

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Spontaneous cocrystallization ?

The spontaneous cocrystallization has been reported after mixing of pure active substances and coformer under a controlled atmospheric environment, when no mechanical forces were applied

Eg. Spontaneous cocrystallization of isoniazid : benzoic a. was observed -Sarcevica, I.; Orola, L.; Nartowski, K. P.; Khimyak, Y. Z.; Round, A. N.; Fabian, L. : Mol. Pharmaceutics 2015, 12 (8), 2981– 2992.

The spontaneous cocrystallization rate can be accelerated by premilling of reagents, by drops of solvent, by temperatureand by air moisture

isoniazid, isonikotinylhydrazid (INH, antibiotic) benzoic acid

Solution evaporation(at fixed temperature and pressure)

Phase diagram is symmetrical –cocrystallization components have thesame solubility.

Cocrystallization is possible !

Cocrystallization components must have similar solubility

Phase diagram is non-symmetrical –cocrystallization components do not have the same solubility.

Cocrystallization is complicated !

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Modifications: evaporation at elevated temperature or elevated pressure, cocrystallization by cooling, cocrystallization by precipitation, reactioncocrystallization …

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Experimental and theoretical phase diagrams

Benčo T., Sládková V., Kratochvíl B.: Chem. Listy111, 829-834 (2017).

TCL – trospium chlorideSA – salicylic acid

Cocrystallization screening on microfluid chips

Combinatorial cocrystallizationscreening by solution technique

240 µg of API + cocrystal former(partner)

Chip wells is resistant to organicsolvents

Analysis on-chip via Ramanspectroscopy in situ

Used in early development

Tested on model API: caffeine, which crystallizes well

Goyal, S.; Thorson, M. R. et al: Cryst. Growth Des. 12, 6023 (2012).

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Co-grinding

Stoichiometric physical mixtures (active substance + coformer) are milled under defined conditions

Retsch mixer mill : time 90 min frequency 25 Hz temperature not allowed to exceed 37 °C

The formation of an amorphous intermediate is the most likely mechanism of cocrystal formation under the cryogenic conditions

Co-grinding under the cryogenic conditions (under liquid N2)

The cocrystallizationprocess may take place via a liquid or amorphous phase, problem: incompleteconversion

Cocrystals prepared by co-grinding: 9-methyladenine + 1-methylthymine, dinitrobenzoic acids + anthracene, nicotinamide + suberic acid, carbamazepine + nicotinamide, etc.

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O

OH O

OH

OOH

N N

Liquid-assisted co-grinding (LAG)

Effect of „molecular lubricant“ during the co-grinding

cyclohexantricarboxylic a. bipyridine

liquid-assisted grinding(with several drops ofMeOH)

grinding

Partial conversion to cocrystal(1:1) after 1 hr

Complete conversion to cocrystal(1:1) after 20 min

Shan N., Toda F., Jones W.: Chem. Commun. 20, 2372 (2002).

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Mechanochemical co-crystallization mechanism during grinding

There is no general theory of the co-crystallization mechanism

Co-melting

Při způsobu smíšené fúze se jedna složka roztaví a nechá se ztuhnout,

než se s ní dostane další roztavená složka, čímž se rozpustí část první

složky. Jakmile je veškerý materiál rekrystalizován, vytvoří se směšovací

zóna. Tato zóna představuje binární fázový diagram pro dvě složky,

přičemž jedna strana směšovací zóny představuje 100% jedné složky a

druhá strana 100% druhé složky s gradientem koncentrace napříč zónou

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Co-melting, an example

Snímek přípravy kokrystalu salicylová k. : nikotinamid společným tavením pomocí mikroskopie s vyhřívaným stolkemFáze: A – salicylová kyselina, B – kokrystal, C – nikotinamid

Berry D. J.; Seaton C. C.; Clegg W.; Harrington R. W.; Coles S. J.; Horton P. N.;Hursthouse M. B.; Storey R.; Jones W.; Friščić T.; Blagden N.: Cryst. Growth Des. 8, 1697 (2008).

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Co-sublimation

From literature: cocrystal urea : succinic a. (2:1) From our laboratory (Dr. Čejka)

Single cocrystal caffeine : malic a.

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Co-heatingThe co-heating method works at temperatures below the melting point of both the active ingredient and the coformer and below the eutectic melting point of the mixture. The most important parameter is the optimization of co-heating temperature and then time.

Maroušková A.: Příprava kokrystalů metodou společného zahřívání. Diplomová práce VŠCHT Praha 2017.

KOF – diklofenakHBA – hydroxybenzoová k.KOF – kofeinGLUT – glutamová k.MALO - malonová k.ŠŤAV – šťavelová k.SALI – salicylová k.BIPY – bipyridinNIKO – nikotinamidUREA – močovinaTHEO – theofylinTCL – trospium chlorid

Cocrystallization by extrusion techniques

Cocrystallization from suspensions

Cocrystallization from supercritical fluids

Spray-drying cocrystallization

Freeze-drying cocrystallization

Cocrystallization by laser irradiation

Electrochemically induced cocrystallization

Sonococrystallization

Cocrystallization from gels, ionic liquids, polymers, etc.

Preparation of cocrystals – advanced techniques

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Cocrystallization by extrusion techniques

Twin Screw Extrusion (TSE) operates at temperatures below the melting point of cocrystallization partners

Carbamazepine:saccharin, theophylline:citric acid, caffeine:oxalic acid, and nicotinamide:cinnamic acid cocrystals were prepared by TSE(Daurio, D.; Medina, C.; Saw, R.; Nagapudi, K.; Alvarez-Núñez, F. : Pharmaceutics 2011, 3 (3), 582– 600).

Hot melt extrusion (HME) combines simultaneous melting and mixing of the cocrystallization partners via the use of a heated screw extruder

+ heaters Carbamazepine and trans-cinnamic acid cocrystal was prepared by HME ( Moradiya, H. G.; Islam, M. T.; Halsey, S.; Maniruzzaman, M.; Chowdhry, B. Z.; Snowden, M. J.; Douroumis, D. CrystEngComm 2014, 16 (17), 3573–3583).

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Isothermal slurry cocrystallization

This technique involves the suspension of the active substanceand coformer, usually in a fixed molar ratio, in a solvent with the solid fraction always remaining in excess.

Eg. cocrystals - theophylline : glutaric a. (1:1) carbamazepin : 4-aminobenzoic a.

(1:1) and (2:1); meloxicam : aspirin; toluenesulphonamide : triphenylphosphine oxide

Cocrystal conversion conditions: time, solution concentration, solvent selection

Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodríguez-Hornedo, N.: Cryst. Growth Des. 2009, 9 (2).Cheney, M. L.; Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.; Zaworotko, M. J. : J. Pharm. Sci. 2011, 100 (6), 2172– 2181. Croker, D. M.; Rasmuson, Å. C. Org. Process Res. Dev. 2014, 18 (8), 941– 946.

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Sonification of slurry

Sládková V. : Pharmaceutical cocrystals. PhD dissertation. VŠCHT Praha 2016.

Polystyrene foam rack with drilled holes for vials, floating in an ultrasonic bath, was successfully applied for cocrystallization. The method was validated on the preparation of previously known cocrystals of carbamazepine with saccharin and nicotinamide.The choice of the solvent and the residence time in the bath had the greatest influence on the preparation of cocrystals. Unlike cocrystallization in the slurry, the ultrasonic bath method allows better contact of the components even when a small amount of solvent is used and the sample is paste-like.

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Cocrystallization from supercritical fluids

The Cocrystallization with Supercritical Solvent (CSS) technique uses the solvent power of supercritical CO2 to suspend the active substance and the coformer as a slurry in liquid or supercritical CO2, avoiding the use of toxic organic solvents.Techniques used: Rapid Expansion of Supercritical Solvents (RESS) Supercritical Antisolvent Cocrystallization Supercritical CO2-Assisted Spray Drying

E.g. Cocrystallization of indomethacin, theophylline, carbamazepine, caffeine,

sulfamethazine, and acetylsalicylic acid with saccharin were reported

Cocrystal conversion conditions: effect of stirring

Neurohr, C.; Marchivie, M.; Lecomte, S.; Cartigny, Y.; Couvrat, N.; Sanselme, M.; Subra-Paternault, P. Naproxen–Nicotinamide Cocrystals: Racemic and Conglomerate Structures Generated by CO2 Antisolvent Crystallization. Cryst. Growth Des. 2015, 15 (9), 4616– 4626.

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Amorphous cocrystals ?

Properties of amorphous phases:

higher dissolution rate (faster onset of action , improved bioavailability )

higher chemical instability (higher molecular mobility, shorter expiration)

higher physical instability (the tendency for phase transition to a crystalline phase)

technological problems in manufacture ( eg., the need of the protective atmosphere )

Amorphous co-crystals have not yet been reported, but they certainly exist !

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Cocrystal analytics

single crystalCocrystallization from solution

(co-sublimation, co-melting)

Cocrystallization by co-grinding

(and other techniques) microcrystalline powder

Single crystal: one pure phase crystal structure analysis, stoichiometry

Powder: one pure phase

Powder: phase mixture phase analysis (degree of conversion to cocrystal)

crystal structure analysis, stoichiometry

The most widely used technique for the cocrystal analysis is X-ray powder diffraction (and IR, Raman

spectroscopies, ssNMR spectroscopy)

input – single crystal

Determination of the crystal structure by the X-ray single crystal diffraction

X-ray diffraction

patterns

distribution of electron density

visualization by molecular graphics

(xyz) =(1/V) Fhkl exp [-2i (hx + ky + lz)]

direct methodscharge flipping

h k l

Fourier synthesis

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X-ray diffractometer

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X-ray single crystal diffraction study of the cocrystal trospium chloride : salycilic acid (1:1)


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X-ray powder diffraction study of the cocrystal synthesis by co-heating

Červeně: fyzikální směs SALI + NIKO (1:1)B. t. SALI 158,6 °CB. t. NIKO 128°C

Zeleně: vzorky po zahřívání fyzikální směsi:(1) 80o C(2) 100o C(3) 120o C

Fialově: kokrystalSALI:NIKO (1:1)(porovnání s literaturou)

Maroušková A.: Příprava kokrystalů metodou společného zahřívání. Diplomová práce VŠCHT Praha 2017.

Study of crystal and molecular structure - from powder X-ray diffraction data (non-standard technique)

Methylergometrine maleate

N+H

HN

HCH3

CH

O

NH

C

CH2CH3

CH2OH

H

COO-

COOH

X-ray powder data

structure, DOF = 20

The structure from powder data is less accurate than from single crystal and moreover, the solution is limited by DOF (Degrees of Freedom) ≈ 40, but the primary

cocrystallization product is the powder

DOF parameters

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Pure phase or mixture ? One phase : after indexing all peaks !

Miller indices

Pure phase or phase mixture ? - indexation

a) When powder data indexing is successful - very likely one phaseb) When powder data indexing is unsuccessful - very likely a phase mixture

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Rietveld fit

The final Rietveld plot of the ivabradine hydrochloride (S) :mandelic acid (1:1)cocrystal, showing the measured and the calculated data. The calculated Bragg positions are shown by vertical bars.


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Conclusions

Cocrystals offer many variations how to improve physicochemical properties of APIs(e.g., solubility, bioavailability, physical stability)

Cocrystals currently have the greatest potential for further development of API portfolio

Cocrystals open up new possibilities in patenting intellectual property and reviewing existing patent protection of APIs and dosage forms

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Srinivasulu Aitipamula et al.:

Polymorphs, Salts, and Cocrystals: What’s in a Name?

Crystal Growth & Design. 12, 2147 (2012).

Documents

Structure and polymorphism of solid pharmaceutical substances