B-Cyclodextrins as a Solubilisation Tool for Insoluble APIs.pdf

7/24/2019 B-Cyclodextrins as a Solubilisation Tool for Insoluble APIs.pdf

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-Cyclodextrins as a Solubilization Tool

for

Insoluble APIs

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One of the main challenges in drug delivery is to guarantee the bioavailability of the

active ingredients, especially when they are poorly soluble and/or with a limited

gastrointestinal permeability. To improve aqueous solubility and thus the

therapeutic effectiveness of such compounds, a number of formulation strategies

have already been largely tested. It is a big challenge to find the right solubilizationtool for these active ingredients.

We will first explain why to choose -Cyclodextrins as a solubilization tool, and all

you need to know to successfully complexate your active ingredient with

-Cyclodextrins. Then using concrete examples will ease the understanding of the

tools used to study inclusion on -CDs: phase solubility, stability constant, and

complexation efficiency, complexation processes in liquid and solid state.

The Biopharmaceutics Classification System (BCS) predicts oral drug absorption

based on the chemicals aqueous solubility and intrinsic permeability through the

gastrointestinal mucosa. Two studies have been realized with highly permeable

drugs with limited water solubility, considered as BCS class II : Zotepine and

Zaleplon. These studies demonstrate why the Roquettes KLEPTOSE range

(chemically modified Beta Cyclodextrin) is the best solution for improving solubility

enhancement.

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-CDs) -Cyclodextrins are cyclic oligosaccharides with a bucket-like structure having ahydrophobic internal cavity and a hydrophilic exterior. This unique structure allows for the

ormation of inclusion complexes, where lipophilic compounds are non-covalently bound withinhe cavity.

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-Cyclodextrins (-CDs) are used to:

Increase aqueous solubility of APIs

Increase chemical and physical stability of APIs

Reduce toxicity (e.g: local irritation after topical or oral

administration)Enhance drug delivery to and through biological

membranes

Mask bad taste or odor

Convert liquid drugs to amorphous powders


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-Cyclodextr ins available on the market:

Native -cyclodextrin

-cyclodextrin (B-CD, KLEPTOSE, Roquette)

Modified -cyclodextrin

Hydroxypropyl--cyclodextrin with a 0.9 degree of molar

substitution (HP-CD, KLEPTOSEHP, Roquette)

Hydroxypropyl-- cyclodextrin with a 0.62 degree of molar

substitution (HPB-CD, KLEPTOSEHPB, Roquette)

-Cyclodextrin Sulfobutyl Ethers Sodium Salts (SBE)

Methyl--cyclodextrin (KLEPTOSE

Crysmeb, Roquette product under development showing interesting inclusion

properties)

What do you need to know about your API to successful ly complexate it with

cyclodextrins (CDs)?

Small molecules:

how many atoms contains: more than 5 atoms (C, P, S, and N) to form the skeleton ofthe drug molecule

how many condensed rings: less than 5

water solubility: less than 10mg/ml

melting point temperature: below 250 C

molecular weight: between 100 and 400

electrostatic charge: positive, negative, neutral

log PpKa

stability issues: chemical, photo, etc.

Large molecules:

the side chain in macromolecules may contain suitable groups which can interact with CDs in

aqueous solutions and form a partial complex with CDs.

Source: Lovatt,M., Cooper,A. and Camilleri,P. (1996) Eur. J. Biophys., 24, 354357

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How are the complexes formed?

n the presence of water, CDs (host molecule) can form inclusion complexes with many drugs

guest molecule) by taking up the molecule, or more frequently some lipophilic part of the

molecule, into the central cavity by a steric and a thermodynamic interaction. Drug molecules

n the complex are in rapid equilibrium with free molecules in the solution. No covalent bonds

are formed or broken during the complex formation.

Source: Frmming and Szejtli: Cyclodextrins in Pharmacy Kluwer Acad. Press, Dordrecht, 1994.

What type of inclusion complexes can -CDs form with an API?

What forces are involved in the complex formation?

Release of enthalpy-rich water molecules from the cavity

Electrostatic interactions

Van der Waals interactions

Hydrophobic interactions

Hydrogen bonds

Release of conformational strain and charge-transfer interactions

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What solubilization solution can -CDs offer?

API formulation in Liquid phase and as Solid Dispersions

CASE STUDIES:

Using concrete examples will ease the understanding of the tools used to study inclusion on

-CDs: phase solubility, stability constant, and complexation efficiency, complexation processes

n liquid and solid state:

Case study 1: Zotepine as Model Drug for -CDs Solubi lization

Case study 2: Zaleplon as Model Drug for Cyclodextrin Solubi lization

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: Zotepine as Model Drug for -CDs Solubilization

Zotepine is an atypical antipsychotic drug used in the treatment of

cute and chronic schizophrenia via blocking dopamine D2 receptors in

he central nervous system

Commercially available as a tablet in 25mg, 50mg and 100mg

Brand name : Nipolept, Losizopilon, Lodopin, Setous, Zoleptil

Due to its low solubility and extensive first pass metabolism its oral

ioavailability is 7-13%

Physical-chemical properties

Mol. Wt. : 331.86

Log P: 5.6

BCS class II (Low Solubility and High Permeability)

Zotepine is equipotent and price competitive compared to other

ntipsychotics and its solubility enhancement by native and modifiedetacyclodextrins can facilitate a better marketability.

What is the phase solubility?

Phase solubil ity evaluation (liquid state solubilization) using Zotepine as a model API

The phase solubility assessment is designed based on Higuchi and Connors method (T.

Higuchi and K.A. Connors: Phase-solubility techniques. Adv.Anal.Chem.Instrum.4, 117-212,

1965) (Fig. 1). Excess amount of API is added to aqueous solutions of increasing CDs

concentrations (10mM up to 50mM (or 200mM) and deionized water (pH 6.5) and optional

depending on the formulation requirements (API pKa) in buffer as controls (Fig.1 and Fig.3).

The vials are mixed for 1, 3 and 7 days at RT (25C) in order to evaluate the mixing time

needed to reach solubilization saturation. Aliquots of these solutions are filtered through0.45mand analyzed by HPLC. Then the concentration of the solubilized API (expressed in

mM or M) is plotted for each CD concentration (in mM or M) and the resulting graph is

representing APIs Phase Solubility curve in the respective CD (Fig.3). Changes in

temperature and pH can lead to a different profile of the Phase Solubility Curve.

Fig Vials set up for Phase Solubility evaluation at RT (25C) in deionized water (pH 6.5).

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Fig 2

. Samples set up for HPLC solubility evaluation, stability evaluation and lyophilization

. Phase-solubility profiles of Zotepine in BCD,HPBCD, Crysmeb and SBE at RT (25oC) in deionized water (pH 6.5).

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Does phase solubility profile prove the inclusion complex formation?

he phase-solubility profiles do not verify formation of inclusion complexes. They onl

escribe how the increasing cyclodextrin concentration influences drug solubility.

ecausecyclodextrins are also known to form:

- Non-inclusion complexes- Complex aggregates

ble to dissolve drugs through micelle-like structures.

What profile the phase solubility curve can be?

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hat is Stabili ty Constants (K1:1) and Complexation Efficiency (CE)?

om the Phase Solubility curve Fig 3. we can calculate as per Eq1 and Eq 2:

here m is the slope of Phase Solubility curve as determined by linear regression and S0 is th

ug solubility in DI water or buffer as determined after (1 to 7) days of mixing (depending at wha

me point the saturation solubility is reached).

Table 1

Zotepine Solubility Enhancement at RT (25oC) in deionized water (pH 6.5).

Table 2

. Zotepine complexes K 1:1 and CE at RT (25oC) in deionized water (pH 6.5).

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Do we need stability evaluation of the API solubilized by -CDs in liquid

hase?

API solubilization is useless if the complex is not stable.

As per Fig 2 samples corresponding to each CD molarity in Phase Solubility experiment are pu

n stability at 25C and 40C for 30 days and 60 days in order to evaluate API:CD complexe

tability in aqueous phase (Fig. 4).

Fig 4. Zotepine complex stability evaluation at 25C and 40C.

API:CD complexes are not stable in l iquid phase do we have an alternative?

es, we lyophilize the liquid phase and we reconstitute it in a liquid vehicle just before IV

dministration.

s in Fig 2 samples corresponding to each CD molarity are lyophilized and then put on stability a

5C and 40C for 30 days and 60 days in order to evaluate API:CD complexes stability in dr

hase.

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How to prove complex formation?

By Differential Scanning Calorimetry (DSC), we can see the API peak disappearing due to

API:-CDs complexation.

Fig 5

DSC Thermograms of Lyophilized Zotepine Phase Solubility Samples

ZOTEPINE Phase Solubility Conclusions:

An AL type phase solubility was observed with all tested cyclodextrins(1mol: 1mol of API:CD ratio).

A high complexation efficiency and stability constants were obtained for BCD and Crysmeb.

Compared to its solubility in water Zotepine solubility increased by ~2871, 1543 and 1240

times in presence of Crysmeb, HPBCD and SBE respectively.

The stability of the complexes formed in presence of Crysmeb>SBE>HPBCD>BCD following

30 and 60 days at 25C and 40C.

The results are offering to the formulator a wide choice in cyclodextrin selection for Zotepine

solubilization.

The complex formation is confirmed for both Crysmeb and HPBCD by DSC

Both Crysmeb and HPBCD would be ideal candidates for Zotepine solubi lization.

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ow can we solubilize an API by solid dispersion inclusion complexes?

y spray drying, freeze drying, kneading, physical mixture, etc. For all these procedures:

Find a volatile hydrophilic organic solvent in which your API is soluble

Prepare a saturated solution of the API in that organic solvent

Evaluate the ratio of the organic solvent (loaded with API) miscible with water (loaded with CD

to get a clear solution (to avoid API precipitation out) in order to comply to AL complexatio

profile (1mol: 1mol of API: CD ratio) as per the Phase solubility diagram ( Fig.3 ) for Zotepine.

ow to get API:CDs complexation by Physical Mixture?

imply mix in a V blender or Turbula mixer the two powders in the molar ratio as per phas

olubility. Depending on the API properties, the rate of encapsulation may be lower compared t

ther techniques as Spray drying (SD), Freeze drying (Lyo), Physical mixture/kneading (PM).

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ow to get API:CDs complexation by spray drying (solubilization from l iquid t

olid state)?

ow to get API:CDs complexation by freeze-drying (solubil ization from l iquid

solid state)?

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ow do I decide which method is the best to solubil ize an API as a solid

spersion?

he best method to create solid dispersions is decided based on DSC and dissolution assessmen

Thermograms for Zotepine Crysmeb Solid Dispersions Fig 7 Thermograms for Zotepine HPBCD Solid Dispersion

Fig 8

Dissolution evaluation of Solid Dispersions of Zotepine in different cyclodextrins

OTEPINE Complexation by solid dispersion methods Conclusion:

Zotepine:HPBCD solid dispersion complexes prepared by spray drying can make this API a

very good candidate for tablet formulation with improved drug solubility and dissolution profile

The data obtained following DSC clearly demonstrate the amorphous nature and complexation

of the drug with cyclodextrin

The dissolution efficiency ranking is :

for HPBCD = Spray Drying (SD) > Lyophilization > Physical Mixture (PM)

for Crysmeb = Spray Drying (SD) > Physical Mixture (PM)

HPBCD is the best solution for Zotepine formulation in a solid dispersion

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: Zaleplon as Model Drug for Cyclodextrin Solubilization

Zaleplon is a hypnotic or sedative medication that induce sleep. It is used for

treating insomnia

It is a potent sedative or hypnotic, commercially available as a tablet at 5mg,

10mg and 20mg (Sonata)

Physical-chemical properties

- Mol. wt.: 305.34

- Log P: 1.53-2.0BCS class II (Low Solubility and High Permeability)

Oral Bioavailability is 30% due to low solubility and extensive first passmetabolism

Fig 9 Phase-solubility profiles of Zaleplon in BCD,HPBCD, and Crysmeb at RT (25oC) in deionized water (pH 6.5).

Table 3. Zaleplon Solubility Enhancement at RT (25oC) in deionized water (pH 6.5).

clusion study of Zaleplon: phase solubility determination

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Table 4

Zaleplon complexes K 1:1 and CE at RT (25C) in delionized water (pH 6.5)

Fig 10

DSC Thermograms of Lyophilized Zaleplon Phase Solubility Samples

omplex characterization: stabili ty constant and complexation efficiency

omplex formation analysis by Differential Scanning Calorimetry (DSC)

ethod

The complexation efficiency and stability constants are high when complexed with Crysmeb

and HPBCD

The DSC chromatogram shows the peak disappearance and proves the API:BCDs complexatio

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ZALEPLON phase solubility Conclusion:

Zaleplon displays an AL type phase solubility profile in all tested cyclodextrins

The complexation efficiency and stability constants are high when complexed with Crysmeb

and HPBCD

Zaleplon solubility augmented by ~ 9, 5 and 3 times in presence of Crysmeb, HPBCD and

SBE respectively, compared to its solubility in water.

The stability of the complexes after 30 and 60 days at 25C and 40C is ranking as follows:

Crysmeb > HPBCD > BCD SBE

BCD solubilization potential is equal to SBE but is lower than HPBCD and Crysmeb.

As confirmed by DSC both HPBCD and Crysmeb are very good solubil ization options

for improving Zaleplon solubility enhancement.

Fig 11

Zaleplon:CD complex stability evaluation at 25C and 40C.

Complex stability evaluation

The stability of the complexes after 30 and 60 days at 25C and 40

C is ranking as follows:

Crysmeb > HPBCD > BCD SBE

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Zaleplon sol id dispersion inclusions prepared by: spray drying (SD), freeze

drying (LYO), physical mixture (PM=kneading)

Fig 12

Thermograms for Zaleplon-Crysmeb Solid Dispersions

Fig 13 Thermograms for Zaleplon-HPBCD Solid Dispersions

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Fig 14

Dissolution evaluation of Solid Dispersions of Zaleplon in different Cyclodextrins

ZALEPLON complexation by solid dispersion methods Conclusion:

Solid dispersions of Zaleplon complexes with Crysmeb and HPBCD by spray drying are very

good candidates for drug solubility increase and improved dissolution profile which will result in

optimized solid dosage forms for its oral delivery

DSC confirms the change in crystalline nature of the drug by the complete disappearance of

Zaleplon peak in spray drying (SD) thermograms

For both CDs (Crysmeb and HPBCD) the dissolution efficiency ranking is:

Spray Drying (SD) > Physical Mixture (PM)

Due to the large amount of organic solvent needed for Zaleplon solubilization, the lyophilized

solid dispersions did not perform as expected.

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CONCLUSION

As demonstrated in the case studies of this document, -Cyclodextrins are fully

adapted tools to increase the aqueous solubility of APIs and their physico-chemical

stability.

They can also be used to reduce toxicity (e.g: local irritation after topical or oral

administration) and to mask material bad taste or odor.

Several pharmaceutical products containing Hydroxypropyl Betacyclodextrin have

already received market approval from several regulatory authorities and have

successfully reached the market.

The patent situation has evolved, in favour of more uses of HPBCD. This new

context makes this excipient an easily accessible formulation aid for the

development scientist.

Roquette provides a range of KLEPTOSE HPBCD derivatives suitable for the

cosmetics and the pharmaceutical industries, including a PYROGEN FREE grade

for parenteral applications. KLEPTOSECrysmeb is a product under development

showing interesting inclusion properties.

Roquette is in a privileged position to discuss the specific needs of the

pharmaceutical and cosmetics industry for information on scientific assistance,

regulatory and patent issues.

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eferences (Roquettes case studies)

etermination of the Thermodynamic Solubility and the Affinity (Bind ing) Constants of Carbamazepine,

nazol and Albendazole in Hydroxypropyl Beta Cyclodextrin (KLEPTOSEHPB) Solutions; Carmen Popescu

ssan Almoazen, Wenli Lu, Anthony Samsa , Leon Zhou, Ashish Joshi, James Johnson, AAPS 2011, Washington

omplexation of Furosemide with SBE--CD Studied by Phase Solubility and Solid Dispersion Methods ; Rui

u, Carmen Popescu, Jean-Yves Pierquin, Xia Zhao, Michael Clarke, Hassan Almoazen, Ed Brunson, James R

nson AAPS 2011, Washington

ffect of Preparation Method on Physical-Chemical

perties and Dissolut ion Profile of Furosemide-Sufobutylether--cyclodextrin (SBE--CD) Solid Dispersion

Zhu, Carmen Popescu, Jean-Yves Pierquin, Xia Zhao, Michael Clarke, Hassan Almoazen, Ed Brunson, James R

nson, AAPS 2011,

shington

he Influence of -Cyclodextrin Side Chain Substitu tions on the Complexation Effic iency of a Model BCS

ss II Compound; C. Popescu, C. Wiley, l. Zhou, P. Lefevre, and L. Felton, AAPS 2011,Washington

hysicochemical Properties that Influence Cyclodextrin Complexation ; C. Popescu , C. Wiley , P. Lefevre , A. J

pfinger, L. Zhou1 , E.X. Esposito , and L. Felton ;AAPS 2012 Chicago

orazepam Complexation w ith Hydroxypropyl --cyclodextrin (HP--CD) and Sufobutylether--cyclodextrinBE--CD): Phase Solubil ity Parameters Evaluation; Carmen Popescu , Wenli Lu, Leon Zhou , Hassan Almoazen

mes Johns; AAPS 2012 Chicago

fluence of Cyclodextrin Complexation Method on the Physical Properties and Dissolution Profile of a BCS

ss II Model Drug; C. Popescu , C. Wiley , S. Potharaju , P. Lefevre , L. Zhou, D. Peterson, and L Felton; AAPS

2 Chicago

re Cyclodextr ins a Viable Tool for Zotepine Solubi lization? Prashanth Manda, Carmen Popescu, Abhishek

uri, Leon Zhou, Michael A. Repka, S. Narasimha Murthy,; AAPS 2013, San Antonio

reparation And Charecterization Of Zotepine Solid Dispersions By Cyclodextrin Complexation ; Carmen

pescu, Prashanth Manda, Abhishek Juluri, Leon Zhou, Michael A. Repka, S. Narasimha Murthy; AAPS 2013, Sanonio

aleplon (BCS Class II Model Drug) Solubility Enhancement By Native And Modified -Cyclodextrins; Carme

pescu, Prashanth Manda, Abhishek Juluri ,Leon Zhou , Michael A. Repka ,

Narasimha Murthy; AAPS 2013, SanAntonio

reparation And Characterization Of Zotepine Solid Dispersions By Cyclodextrin Complexation ; Carmen

pescu ,Prashanth Manda, Abhishek Juluri, Leon Zhou, Michael A .Repka, S. Narasimha Murthy; AAPS 2013, San

onio

olid Dispersion Of Zaleplon Cyclodextrin Complexes And Evaluation Of Their Efficiency; Prashanth Manda,

rmen Popescu, Abhishek Juluri, Leon Zhou, Michael A. Repka, S. Narasimha Murthy; AAPS 2013, San Antonio

elecoxib (BCS Class II Model Drug) Solubili ty Enhancement By Cyclodextrin Complexation ; Abhishek Juluri,

rmen Popescu, Prashanth Manda, Leon Zhou,Michael A. Repka , S. Narasimha

rthy; AAPS 2013,San Antonio

reparation And Charecterization Of Zaleplon Solid Dispersions By Cyclodextrin Complexation ; Carmen

pescu ,Prashanth Manda, Abhishek Juluri , Leon Zhou, Michael A .Repka , S. Narasimha

rthy; AAPS 2013, San Antonio

mpelopsin (Amp) Solubi lization By Inclusion Complexes; Carmen Popescu, Abhishek Juluri, Craig Buske, Leo

ou, Philippe Lefevre, S. Narasimha Murthy; AAPS 2014, San Diego

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