Solid pharmaceutical phases – anhydrates, hydrates, salts, cocrystals,

amorphates

Bohumil Kratochvíl bohumil.kratochvil@vscht.cz

Course: Chemistry and Physics of Solid Pharmaceutical Substances, 2017

Chemical and physical forms of solid API‘s

Chemical and physical form of the API must be selected during the drug discovery in the phase called „drug candidate“

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The first choice is to formulate API as anhydrate (free acid , free base or a neutral molecule ) - if anhydrate is from some reason insufficient, other types of API‘s are considered (other polymorphs, hydrates , salts, amorphates ... )

Pharmaceutical anhydrates

ibuprofen – free acid

CH3

CH3

O

OH

CH3

nicergolin – free base guaifenesin – neutral molecule

O

CH3

O

OH

OH

pKa = 4,41 pKa = 8,42

pKa = 6,33 3

Examples of formulations from anhydrates (about 40 % of all solid formulations)

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Ibuprofen:

Nicergolin:

Guaifenesin:

Pharmaceutical solvates (hydrates)

Certain molecules have the ability to crystallize from different solvents, as solvates (or pseudopolymorphs or solvatomorphs). Solvates are used predominantly as precursors for manufacture of some hardly obtanaible polymorphs (by desolvatation method).

azithromycin dihydrate (antibiotikum), Azitrox (Zentiva)

terpin monohydrate (expektorans), Coldrex (GlaxoSmithKline)

The reason for the low number of formulations of hydrates (about 5%) is fear concern about the potential for dehydration 5

The pharmaceutically acceptable solvates are hydrates only, exceptionally ethanol solvates (e.g. indinavir sulfate ethanolate)

Examples of formulations from hydrates (about 5 % of all solid formulations)

One tablet contains (API‘s): Paracetamolum 500 mg Coffeinum 25 mg Phenylephrini hydrochloridum 5 mg TERPINUM MONOHYDRICUM 20 mg Acidum ascorbicum ethylcelluloso obductum 38 mg, (odpovídá Acidum ascorbicum 30 mg)

API: AZITHROMYCIN DIHYDRATE – antibioticum

API: Zoledronic acid monohydrate - bisfosfonates

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Stoichiometric and non-stoichiometric hydrates

Stoichiometric ( crystalline) hydrate - the ratio between the substance and the water is expressed precisely defined ratio in the crystal structure - useful for formulation (eg. monohydrate, dihydrate etc.) Non-stoichiometric hydrate - water is only captured (trapped) in the structure of substance and its content is variable (interstitial solid solutions ) – unuseful for formulation (eg. 0.432 hydrate etc.)

Interaction of water with a solid phase: Water absorption in the bulk : - Formation of hydrates , hydrolysis, inclusion, deliquescence , crystallization amorphous phases Water adsorption on the surface : - Capillary condensation , hygroscopicity, increasing molecular mobility of the substance (plasticizing), induced physical and chemical degradation , local amorphization

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When free acids, free bases or neutral molecules have available

free H-donors or H-acceptors form stable hydrates

Why form free acids , free bases or neutral molecules hydrates ?

dipicolinic acid proton acceptor available

proton acceptor available

proton acceptor available

Anhydrate

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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Etter‘s rules for H-bonding (Acc. Chem. Res., Vol. 23, No. 4. (1990)

1. All good proton donors (D) and acceptors (A) are used in hydrogen bonding

2. Six-membered intramolecular hydrogen bonds rings form in preference to intermolecular hydrogen bonds

3. The best proton donors and acceptors remaining after intramolecular hydrogen-bond formation form intermolecular hydrogen bonds to one another

Six-membered-ring Intramolecular bonds Intermolecular bonds

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hydrate

anhydrate

Other examples of hydrates – water is very strong both proton donor and acceptor

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Other examples of hydrates – water is very strong both proton donor and acceptor

anhydrate

hydrate

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Other examples of hydrates – water is very strong both proton donor and acceptor

anhydrate

hydrate

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The most stable phase in the terguride system is monohydrate

E: terguride . EtOH A: terguride . 2/3 H2O M: terguride . MeOH

T> 40o C water suspension 1 hour in air

or 3 days at 75% RH

B: terguride . H2O 6 hrs, 70o C

water suspension several months at 75% RH water suspension

C: terguride anhydrous D: terguride . H2O F: terguride . 2/3 H2O

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Pharmaceutical salts and hydrated salts

The basic prerequisite for salt formation are the ionizable groups in the molecule

Terguride hydrogen maleate (the active ingredient is a cation -protonated base), 75 % formulated salts

Calcium atorvastatin (the active ingredient is an anion – deprotonized acid), 25 % formulated salts

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Pharmaceutical salts and hydrated salts

The main reasons for the choice of the salt formulation : The salts are generally more soluble in water than the free acid or free base or neutral molecules , because they are more easily ionizable !

Solubility and dissolution rate of salts is dependent on pH ( pHmax )

Unstable liquid base or acid can form stable solid salts , eg viscous liquid scopolamine (base ) forms crystalline hydrobromide, liquid valproic acid forms solid sodium and magnesium salt

valproic acid scopolamine

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• Only such partners (couterions) for the synthesis of pharmaceutical salts are acceptable who meet the directive GRAS ( Generally Recognized as Safe) : http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm

• Experience shows that for a formation of the stable pharmaceutical salt, it is necessary to be the difference pKa = |pKa (substance) - pKa (ionization partner)|

Basic rules for the selection of a suitable pharmaceutical salts

Relation between solubility, pKa a pHmax

Polymorphism in the Pharmaceutical Industry (Hilfiker R., ed.). Wiley-VCH, Weinheim 2006. 16

Pharmaceutical salts and hydrated salts

For each salt , there is a pH value at which its solubility is the highest. This value is called pHmax , so dissolution of drug may be targeted to a particular point in GIT

pHmax

pHmax

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Pharmaceutically accepted couteranions

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Frequency of counter anions used in dosage formulations

(Handbook of Pharmaceutical Salts: Properties, selection and use. (Stahl P.H. & Wermuth C.G.,

Eds). Wiley/VCH/VHCA, Weinheim/Zürich 2002.)

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Pharmaceutically accepted counter cations

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Frequency of counter cations used in dosage formulations

(Handbook of Pharmaceutical Salts: Properties, selection and use. (Stahl P.H. & Wermuth C.G.,

Eds). Wiley/VCH/VHCA, Weinheim/Zürich 2002.)

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bambuteroli hydrochloridum benzatropini mesilas benzododecinii bromidum benzylpenicillinum kalcium bupivacaini hydrochloridum cerivastatinum natricum cerii nitras hexahydricus ephedrini hydrochloridum hydrocortisoni butyras chinini sulfas kalii orotas

Examples of formulations from salts and hydrated salts (about 50 % of all solid formulations)

atorvastatinum calcicum trihydricum codeini phosphas hemihydricus natrii aledronas monohydricus bisfosfonát apomorphini hydrochloridum hemihydricum dantrolenum natricum trihemihydricum kalii hydrogenaspartas hemihydricus calcii hydrogenophosphas dihydricus cerii nitras hexahydricus ferrosi sulfas heptahydricus riboflavini natrii phosphas dihydricus

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Pharmaceutical counteranions - organosulphonates

methansulphonate (mesylate)

benzensulphonate (besylate)

naphtalensulphonate (napsylate)

toluensulphonate (tosylate) camphorsulphonate (camsylate)

Trimetaphan Camsylate (Arfonad)

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ethanesulphonate (esylate)

Strategy of the optimal salt choice 1.

2.

3.

4.

The winner salt is the sulfate

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Glycosidic derivatives

Glycosidic derivative of hepatoprotective silybin . Solubility of silybin is very low ( 430 mg / l). Silybin glycosides are 4-30 times more water soluble than pure silybin

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Pharmaceutical cocrystal - definition

Pharmaceutical cocrystal is a multicomponent compound of the host : guest type, formed from two or more reactants that are solids at ambient conditions. Stoichiometry of cocrystals is mostly simple (1:1, 2:1, 3:2 etc.)

alternative terms: mixed crystals, clathrates, inclusion compounds, molecular compounds, molecular complexes, supramolecular adducts …

Example: carbamazepine : saccharine (1:1)

(active molecule)

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Cocrystallization formers (coformers) – must be pharmaceutically accepted

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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Cocrystal carbamazepine : saccharine (1:1)

As cocrystals held together

- - -

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

H-můstky H-můstky H-můstky H-můstky

The molecules in co-crystals retain their covalent identity

Cocrystallization or recrystallization

Unfortunately, we do not know all details the process of crystallization and the nature of the chemical bonds

Why cocrystals are interesting for pharmacy ?

Active substance Cocrystal New 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

Cocrystals are not pharmacodynamically more effective than an active substance itself, but they modify (optimize) its technological or function parameters

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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“

Cocrystals can modify dissolution profile

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

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

Preparation of cocrystals – universal cocrystallization strategy does not exist !

Solution evaporation

Solid-state grinding

Sublimation

Melting

Unfortunately, almost all cocrystals which could be prepared by simple

classical techniques are already described

1) Classical cocrystallization techniques

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Liquid assisted solid-state grinding, cryogrinding

Cocrystallization in suspension

Sonococrystallization

Slow or quench solution cooling

Cocrystallization from gels, ionic liquids, polymers, supercritic fluids etc.

Cocrystallization in twin screw extruder

Spray drying cocrystallization

2) Advanced cocrystallization strategies

Preparation of cocrystals – universal cocrystallization strategy does not exist !

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O

OH O

OH

OOH

N N

Liquid-assisted solid-state grinding

Effect of „molecular lubricant“ in the common grinding

cyclohexantricarboxylic a. bipyridine

liquid-assisted grinding (with several drops of MeOH)

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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Cocrystallization of trospium chloride with urea

Trospium chloride – urinary antispasmodic

Urea

Cocrystal trospium chloride : urea (1:1)

Crystal structure of cocrystal 36

Cocrystallization of trospium chloride with urea

1. Skořepová, E., Čejka, J., Hušák, Eigner, V., Rohlíček, J., Šturc, A., Kratochvíl, B.: Trospium Chloride: Unusual Example of Polymorphism Based on Structure Disorder. Cryst. Growth Des. 13, 5193–5203 (2013). IF=4,689

2. Sládková V., Cibulková J., Eigner V., Šturc A., Rohlíček J., Kratochvíl B.: Application and Comparison of Cocrystallization Techniques on Trospium Chloride Cocrystals. Cryst. Growth Des. In print (2014). IF=4,689

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). IF=1,552

Dissolution profiles

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Amorphous phases and amorphous hydrates – basic facts

Chemical and physical forms of the API‘s (ahydrates, hydrates, salts, cocrystals) can exist both as crystalline or as amorphous phases

Boundaries between ordered (crystalline) phase and unordered (amorphous) phase is fuzzy ( so called: semi-crystalline phase)

Amorphous phase is generally more and faster soluble to compare with crystalline phase (better dissolution profile), but has the following disadvantages - high molecular mobility (absorbed water), which causes chem. and phys. instability (shorter expiration)

The crystalline phase contains often amorphous regions ( e.g., resulting in grinding). The content of the amorphous phase in the crystalline bulk substance affects its stability Amorphous hydrates have constant water content for a long time , while amorphous phase water content is variable depending on the RH (amorphous form of hydrated trisodium alendronate

In the pharmaceutical formulations dominate the crystalline phase before amorphates (amorphous phase consists of only a few % of the total portfolio - but are important) , semi-crystalline phase formulations are not used in formulations 38

Advantages of amorphous API‘s

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

Dissolution profile of amorphous and crystalline indomethacin (Fukuoka et al.: Pharmacobio-Dynamics 9, S5 (1986).

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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 )

Thermal degradation of cefoxitin sodium

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zafirlukast (Accolate, Astra-Zeneca), treatment of asthma, original

itraconazol – (Sporanox, Janssen-Cilag ), to treat infections caused by fungi , original

indomethacin – (Indocin, Merck), antirevmaticum, original

atorvastatin calcium – (Torvacard, Zentiva), hypolipidemicum, generic

Amorphous originals and amorphous generics

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Amorphous phases must be stabilized

For pharmaceutical applications must be the amorphous phase stabilized

by suppressing of the intensive molecular mobility.

Stabilized amorphous mixture is a dispersion of the amorphous phase in the polymer or in a thin layer (coating). The stabilized amorphous mixture is not capable of crystallization.

Microphoto of recrystallized amorphous felodipine without polymer

Microphoto of recrystallized amorphous felodipine with 3% of HPMCAS (hydroxypropylmethylcellulose acetate succinate)

H.Konno, L.S.Taylor: J.Pharm. Sci 95, 2692 (2006). 42

Example: dosage form of atorvastatin calcium

Original, crystalline form, expiration 36 months

093015 SORTIS 10 MG POR TBL FLM 100X10MG PFX CZ R

PL: Calcii carbonas, Cellulosum microcristallinum, Lactosum monohydricum,

Croscarmellosum natricum,, Hyprolosum, Magnesii stearas. Coating: Simeticoni

emulsio, Candelilla cera, Album opadry YS-1-7040 (Hypromellosum, Macrogolum

8000, Titanii dioxidum, Talcum).

Generics, amorphous form, expiration 24 months

(after opening use within 90 days )

0015118 TORVACARD 10 POR TBL FLM 30X10MG ZEH CZ R

PL: Magnesii oxidum ponderosum, Cellulosum microcristallinum, Lactosum

monohydricum, Croscarmellosum natricum, Polysorbatum 80, Hyprolosum

hyposubstitutum, Silica colloidalis anhydrica, Magnesii stearas. Coating: Hypromellosum,

Macrogolum 6000, Titanii dioxidum, Talcum.

In some pharmaceutical formulations amorphous phases are stabilized by

sugars (formation of H-bonds)

Stabilization of amorphous formulations by sugar-excipient

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Coexistence of crystalline and amorphous phases - degree of crystallinity

The X-ray powder diffractograms of amorphous proportion in a crystalline phase. Effects on increased background and extending of diffraction peaks

Pure crystalline phase

Pure amorphous phase

Mixture of crystalline and amorphous phases

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Amorphous phases - synthesis

From melt : quench cooling (glass transition, Tg)

From solution : spray drying, freeze drying (lyophilization), rapid precipitation

From solid: grinding, sublimation, rapid desolvatation

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Quench cooling

Cooling: volume (enthalpy) changes during the cooling melt : TK - Kauzmann temperature , Tg - glass transition (measured by DSC – differencial scanning calorimetry), Tm - melting point (indomethacin, felodipin, nifedipin)

Glass transition is a continuous transition of the 2nd order 46

Tg values of some API and relation to Tm

Relation varies: Tg / Tt = 0,7 – 0,85

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Freeze drying (lyophilization)

a) Rapid freezing of a solution (or fresh food) in liquid nitrogen b) Primary evaporation (sublimation) of the solvent ( water ) at a lower pressure c) Secondary evaporation of residual

Lyophilized food

This highly effective dehydration method involves the removal of water from frozen materials via the direct sublimation of ice

Solution for injection are unstable, but as lyophilized (amorphous) powders are ready-to-use liquid dosage forms (after adding water)

Industrial apparatus for production of lyophilized powders. Lyophilization driving force is the temperature difference between the sample and the condenser 48

Spray drying

Spraying a solution into a hot atmosphere ( air, nitrogen ) . Spherical particles are produced with several m excellent flow properties ,

eg . antibiotics, medical ingredients, additives.

An efficient technology for solid dispersion manufacturing. It allows extreme rapid solvent evaporation leading to fast transformation of an API solution to amorphous solid API- particles.

REES technology – Rapid Expansion of Supercritical Solution (CO2) - microparticles or microspheres eg. poly(l-lactic acid) (l-PLA) with naproxen

apparatures

products

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Grinding

Energy introduced into the grinding of API is about 10% utilizes the surface increase , and 90 % activated thermodynamically metastable excited state of the material

Grinding of the crystalline phase - may or may not happen the glass transition (microgrinding, particles 5-10 mm, nanogrinding particles 100 Å (100 nm )

Amorphous API obtained by grinding: indomethacin , sertraline hydrochloride , atorvastatin calcium , cephalosporins, quinapril hydrochloride , itraconazole, zafirlukast, cilastatin , nelfinavir mesylate, felodipine, nifedipine, cefuroxime axetil, insulin ... )

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Conclusions

Polymorphs ( anhydrates ) , hydrates, glycosylic derivatives , salts and co-crystals represent a wide variety of properties of crystalline substances for final solid dosage formulation Most used pharmaceutical substances are salts, the great potential have co-crystals

Variety selection of APIs allow pharmaceutical companies avoid a patent collision

Amorphous pharmaceutical substance are minor , but important group of APIs

The transition between the amorphous and crystalline phases takes place through the

semi-crystalline phase

The amorphous phase is generally faster soluble than crystalline phase , but it is compensated for its lower chemical and physical stabilities Interesting phases are amorphous hydrates, which keeps constant amount of water for

a long time

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