novel docusate excipients for poorly soluble apis

Novecare

Novel Docusate Excipients for Poorly

Soluble APIs

Nimal Jayasuriya

Outline

Part 1

Docusate • What is Docusate?

• Properties of Docusate

• Examples of use as excipients

Part 2

DocuSolv™

• What is DocuSolv ?

• Properties of DocuSolv

• Examples of use as excipients

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Novel Docusate Excipients for Poorly Soluble APIs

2

Current Drug Formulation Issues

• Poor bioavailability- 40-70% of the API’s have poor

solubility

• Stability

• Safety- Trend toward pharma grade excipients

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Need for improvements in formulation design

Technologies For Improving API Solubility

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IMPROVING SOLUBILITY

Particle milling/ Micronization

Nano particles/ Nano crystals

Spray Drying

API Synthesis/ Salt formation

Novel excipients/ Surfactants

Melt Extrusion

API DESIGN/ENHANCEMENT API SIZE REDUCTION SOLID DISPERSIONS

Surfactants as excipients can play an important role

• Optimize bioavailability using particle engineering

• Controlling colloidal, surface and interfacial properties

DOCUSATE – A Surfactant for the Pharmaceutical Market

Global leader in Docusate, a cGMP grade surfactant for the pharmaceutical market:

• DMF holder

• Meets USP and EP monographs

• CEP pending

• GRAS-listed excipient

• Compatible with a wide range of pharmacologically active drugs

• Proven, tested and stable formulation aid

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Providing Docusate to Pharma for Over 40 Years

DOCUSATE – Structure and Nomenclature

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Docusate - a twin-tailed anionic surfactant

Docusate sodium (USP, Ph.Eur., and BP)

Sodium 1,4-bis(2-ethylhexyl) sulfosuccinate

Dioctyl sodium sulfosuccinate (DOSS or DSS)

Mol. Form.: C20H37NaO7S

Mol. Wt.: 444.6 g/mol

White, waxy flakes or masses; Hygroscopic

Melting point >150°C

Water solubility – 15g/L or 1 in 70 parts at 25°C

Soluble in organic solvents

DOCUSATE – Surfactant Properties

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Excellent solubilizer, wetting agent, dispersant and emulsifier

Critical Micelle Conc. (CMC): 1.2mg/ml at 25°C in water

Minimum Surface Tension: ~ 26 mN/m

The ease with which a product is wetted is a crucial factor in order to

provide good dispersion in a matrix and reduce friction during

mixing.

Docusate is one of the best

wetting agents known

Contact Angle

Docusate – Grades used as Excipient

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• Docusate grades currently in use:

- DSS USP• Waxy rolls of 100% material

- DSS- Granular• Free flowing powder of 85% DSS on 15% Sodium benzoate carrier

– Easy handling

– Reasonable dissolution

– Preservative

Fresh from the dryer

On storage

No change of appearance on storage

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- Granulation Process

- Hot Melt Extrusion

- Nanoparticulate System

Docusate - Use in OSDF - Examples

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Docusate in Wet Granulation ProcessImproved Dispersion of Pure Valsartan

0.1%

DOCUSATE

1%

DOCUSATE

Valsartan in 0.1% solution of Docusate in water: Clumps together as API is poorly wettable

Valsartan in 1% solution of Docusate in water: Finely dispersed and floating

• Pure Valsartan (an angiotensin) is poorly soluble

• BCS Class II at pH < 4; Class III at higher pH

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Docusate in a Wet Granulation Process

Granulation inHigh Shear MixerAPI, DSS + Binder

Weighing

Wet Sieving

Preparation of the granulation fluid

Water, DSS + Binder

Fillers, lubricants etc..

Tray Drying

Dry Sieving

Compression

Blending

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Docusate in Granulation ProcessImproved Solubility of Valsartan:

At pH = 6.8

Provas Commercial sample as reference

Pure Valsartan formulated with DSS almost as good as reference

“Classical” formulations, using only binder, without DSS, give very poor solubility

Interaction of DSS with the binder plays a role

Binder: Isomalt or MCC

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Docusate in Wet Granulation Process

At pH = 6.8 (~ intestine condition)

• Docusate can significantly accelerate the development of target release profile for APIs where wettability is an issue

• Less batch-to-batch variability when API’s wettability is improved during formulation

• Results are ultimately influenced by carrier / binder system

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Docusate in Hot Melt Extrusion (HME)

Ritonavir (anti-HIV) BCS Class IV; water solubility <1mg/L

Exists in a number of polymorphic forms

Has significant (re)crystallization issues thus ideal model compound for HME

Commercial formulated brandname : Norvir®

Ritonavir

Norvir® is a registered trademark of Abbvie Inc.

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• Molten API and polymer are mixed and extruded• Extrudate chopped into small pieces• Further formulated in tablets or capsules

Docusate in Hot Melt Extrusion (HME)

Norvir® is a registered trademark of Abbvie Inc.

• API “fixed” in polymer matrix• May act as carrier to bring into body• May avoid (re)crystallization of amorphous or polymorph API

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HME Process and Components

Component Amount [mg/SD]

Ritonavir 100

Docusate none or 5

Soluplus or Eudragit EPO ca 100

MCC 200 100

MCC 105 92

Carboxymethyl starch Na (Type A)

20

Magnesium stearate 8

Formulation of a 400mg Tablet of Ritonavir

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HME Process – Solubility of Ritonavir

Norvir

Ritonavir

Commercial Norvir® (4th G benchmark) already very well formulated

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Solubility of Formulated Ritonavir in Tablets from HME- Soluplus®

Polymer - Stomach Conditions

RitonavirRitonavir + Soluplus polymer

Norvir®Ritonavir + DSS + Soluplus polymer

Solubility of 100 mg API in 500 ml 0.1 M HCl (pH 1.2) ~ stomach

Ritonavir

Ritonavir + Eudragit EPO polymer

Ritonavir + Eudragit EPO polymer and varying DSS levels

Norvir®

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Solubility of Formulated Ritonavir in Tablets from HME- Eudragit®

Polymer - Stomach Conditions

Solubility of 100 mg API in 500 ml 0.1 M HCl (pH 1.2) ~ stomach

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Docusate in HME Process

• DSS significantly improves the dissolution profiles of BCS Class IV Ritonavir in HME formulations.

• The ideal combination of DSS with HME excipients cannot be predicted in advance and must be evaluated on case-by-case basis.

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Docusate in Nanoparticulate Systems

Reduction in particle size results in a dramatic increase in surface area which in turn increases the material’s dissolution rate, and thus increases “apparent” solubility.

Typical processes include both wet and dry milling processes.Wet processes typically yield lower particle sizes, down ~ 100 nm

Analogous to other applications, stability issues (Ostwald ripening) start playing a role.

Surfactant and stabilizers are needed

18

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Nanoparticulate Example

o Leading product in market is exceeding “solubility limit”

o System made with DSS not only has 50% higher solubility but also faster dissolution rate

Wet Ball Milling process:• Preparation of API pre-

suspension

• Nano-milling

• Conversion of nanosuspension into solid intermediate by spraying onto water soluble carrier in fluidized bed

• Tableting of nanoparticlegranules

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Features of Docusate in Nanoparticulate Systems

• DSS plays an important role in stabilizing nanoparticulate systems.

• DSS should be the preferred surfactant, due to rapid wettability of the API.

• Granulates and tablets stabilized by DSS demonstrate excellent stability during manufacturing and storageunder both standard and accelerated conditions

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• Solubilizing agent for poorly soluble API’s in:- Wet granulation- HME process- Nanoparticulate systems

• Wetting and dispersing agent

• Also used as glidant, disintegrant, emulsifier, or mold release agent in a variety of drug formulations

Summary:Properties of Docusate as an Excipient

Excellent excipient to improve solubility

Biopharmaceutics Classification System (BCS) Positioning of some Drugs Containing DSS

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Class 1FinasterideLevodopaBenserazideTolterodinetartrateSulfometoxazoleThrimethoprim

PrednisoloneSulfadiazineAlprazolam

Class 2NaproxenFenofibrateVerapamilTrandolaprilNimesulideCarisoprodolPrednisoneJosamycinCandesartanCilexetilTrandolapril

NilutamideCarbamazepineSimvastatinNoscapineChlorzoxazoneDesoximetasoneMegestrol AcetateRifampinErythromycinSpironolactoneTolazamide

Class 3ParacetamolBiperidenFerroFumarateCodeineOxycodon

Class 4AspirinMesalazinePyrimethamineMetopimazinePhenobarbital

Hig

h P

erm

eab

ility

Lo

w P

ermeab

ility

High Solubility

Low Solubility(All data exclusively obtained from public medical records)

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FDA Inactive Ingredients List

Ingredient Name Route Dosage FormCAS_Numb

erUNII

Potency Amount

Potency Unit w

DOCUSATE SODIUM ORAL CAPSULE 577117F05Q2T2JA0 8.2MG

DOCUSATE SODIUM ORAL CAPSULE, HARD GELATIN 577117F05Q2T2JA0 0.64MG

DOCUSATE SODIUM ORAL CAPSULE, SUSTAINED ACTION 577117F05Q2T2JA0 0.001MG

DOCUSATE SODIUM ORAL SUSPENSION 577117F05Q2T2JA0 6MG/5ML

DOCUSATE SODIUM ORAL SUSPENSION, SUSTAINED ACTION 577117F05Q2T2JA0 0.77MG/1PKT

DOCUSATE SODIUM ORAL TABLET 577117F05Q2T2JA0 11MG

DOCUSATE SODIUM ORAL TABLET (IMMED./COMP. RELEASE), COATED 577117F05Q2T2JA0 0.5MG

DOCUSATE SODIUM ORAL TABLET, COATED 577117F05Q2T2JA0 0.006MG

DOCUSATE SODIUM ORAL TABLET, FILM COATED 577117F05Q2T2JA0 0.5MG

DOCUSATE SODIUM ORAL TABLET, SUSTAINED ACTION, FILM COATED 577117F05Q2T2JA0 0.03MG

DOCUSATE SODIUM/SODIUM BENZOATE ORAL CAPSULE 121183106656HXR6YXN 85MG

DOCUSATE SODIUM/SODIUM BENZOATE ORAL CAPSULE, EXTENDED RELEASE 121183106656HXR6YXN 0.138MG

DOCUSATE SODIUM/SODIUM BENZOATE ORAL TABLET 121183106656HXR6YXN 8MG

DOCUSATE SODIUM/SODIUM BENZOATE ORAL TABLET, FILM COATED 121183106656HXR6YXN 3MG

The FDA’s Inactive Ingredients data based can be found at:http://www.fda.gov/Drugs/InformationOnDrugs/ucm113978.htm

Above is an excerpt from update through October 31, 2015 for Docusate sodium and Docusate sodium/sodium benzoate.

?

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DocuSolv™ - Novel Docusate Excipients

Docusate DSS USP solid, waxy rolls

Non-optimal handling and slow dissolution

Docusate DSS GranularEasy handling and reasonable

dissolutionNon-optimal effects of sodium

benzoate and preservative

DocuSolv™ Free flowing forms of DSS.

DSS USP DSS Granular DocuSolv

DocuSolv™ giving the formulator better handling and faster dissolution rates

Docusolv™ is a trademark of Cytec Industries Inc.

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DocuSolv™ Enhanced Handling:Novel Form. Fast Dissolution. Increased Consistency.

DSS USP Carrier DocuSolv™

HPMC DocuSolv™ SP-200

PVP-VA DocuSolv™ F-200

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A. Docusate Granular: Spheres and irregular shapes of avg. ca. 100µm

B. DocuSolv™ SP-200: Spheres of 5 –30 µm diameter

C. DocuSolv™ F-200: Fine flakes of various sizes; 3 µm thickness

Particle Sizes

(Magnification 500 x)

A

B C

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• Both carriers in DocuSolv™ SP-200 and DocuSolv™ F-200 are pharmaceutical grade excipients in their own right

• Both have USP and EP monographs.

• No chemical changes during processing

• Can be considered as GRAS

Regulatory Perspective on DocuSolv™

Docusate crystalline

Carrier

XRD of DocuSolv SP-200

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Faster dissolution of DocuSolv™ Complexes

0

10

20

30

40

50

DSS DSS‐Gran Docusolv SP‐200 Docusolv F‐200

47

2520

7

Minutes

Dissolution time

Improved handling and processing for both complexes

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Improved Solubility: DocuSolv™ vs. Docusate

DocuSolv SP-200 DocuSolv F-200

Solubility in Water (g/L) Appearance NTU Appearance NTU

10 Clear liquid 1.0 Clear liquid 0.9



100 Hazy liquid 266 Clear liquid 8.3

DSS is known to have limited solubility in water

• Solubility of DSS in water at 25°C - Approx. 15 g/L, or 1 in 70 parts

DSS-Granular shows limited solubility at 25°C and a turbid appearance at 10 g/L

Solubility of DocuSolv™ SP-200 lies between 50 and 100 g/L

Solubility of DocuSolv™ F-200 >100 g/L

Stable supersaturation of excipient for both complexes

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• Despite presence of significant amount of carrier, equivalent CMC of about 1.0 mg/ml is maintained

• Outstanding surface tension suppressing performance of the DSS molecule is maintained as well (ST << 30 mN/m @ CMC)

DocuSolv™ - Surfactant Properties

Equivalent to Docusate

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Wetting Properties in Water – Contact Angle

Fenofibrate Naproxen Ibuprofen Ritonavir GlipizideDocuSolv™ SP-200 21⁰ 8⁰ 31° 31° 18°DocuSolv™ F-200 46⁰ 21⁰ 46° 51° 39°DSS-Gran <10⁰ 10⁰ 21° 12° <10°DSS USP 24° 11° 32° 22° 19°SLS 52° 33° 60° 34° 34°TWEEN® 80 68° 37° 73° 55° 55°Water 82⁰ 61⁰ 76° 60° 55°

Docusates and DocuSolv™ are better wetting excipients than other surfactants

Contact angle of water and DocuSolv SP-200 on Naproxen

• Sessile drop method

• Solution on a pellet of API

• Contact angle measured using 10µL drops of a 0.1% solution of active surfactant

TWEEN® is a registered trademark of Croda Americas LLC

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SolutionsContact Angle (°)

Ibuprofen Fenofibrate Naproxen Ritonavir Glipizide

DocuSolv™ SP-200 <5 <5 <5 23 <5DocuSolv™ F-200 <5 <5 <5 25 <5DSS-Granular <5 <5 <5 20 <5DSS-100 <5 <5 <5 33 <5SLS 54 47 34 57 43Tween® 20 45 58 48 40 42Tween® 80 68 70 52 51 55pH 1.2 buffer 69 76 63 50 60

Wetting in Stomach conditions

Unsurpassed wetting of DSS and DocuSolv™ on APIs in the stomach

The ease with which a product is wetted is a crucial factor in facilitating the first dissolution in the stomach

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SolutionsContact Angle (°)

Ibuprofen Fenofibrate Naproxen Ritonavir Glipizide

DocuSolv™ SP-200 <5 <5 <5 <5 <5DocuSolv™ F-200 <5 <5 <5 <5 <5DSS-Granular <5 <5 <5 <5 <5DSS-100 <5 <5 <5 <5 <5SLS 60 52 47 41 43Tween® 20 59 58 46 53 50Tween® 80 71 61 52 57 40pH 6.8 buffer 64 72 63 56 63

Wetting in Intestine conditions

Unsurpassed wetting of DSS and DocuSolv™ on APIs in the intestine as well

The ease with which a product is wetted also is a crucial factor in facilitating further dissolution in the intestine

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Solubilization of Ibuprofen by DSS and DocuSolv

Effective solubilizing agents

0

100

200

300

400

500

600

HPMC PVP/VA DSS‐100 SP‐200 F‐200

Maxim

um Ibuprofen solubility (mg / L)

Surfactant

Maximum Ibuprofen solubility in 0.1, 0.5 and 1 % surfactant solutions in pH1.2 buffer

Control

0.1%

0.5%

1.0%

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• Nano-suspensions using several APIs, using DocuSolv™ F-200 as excipient yielded good and facile particle size reduction to < 200 nm with good stability

Improved Stability with DocuSolv™

Stabilizing agent for nano suspensions

Nano-suspension of Glipizide made with DocuSolv™ F-200 stable for over 21 months

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• Using DocuSolv™ SP-200 in drugs formulated from an HME process yielded improved solubility of the API, coming close or equivalent to commercial product

Improved Solubility with DocuSolv™

Positive results in OSDF

Ritonavir

Norvir

w/ 0.5% DocuSolv SP-200

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• Products: DocuSolv SP-200 Granular, DocuSolv F-200 Flake

• Smaller particle size that dissolves faster

• Better handling and reduction in processing time

• Easy to create solutions with higher concentrations

• Enhanced solubility, dispersion and wettability of API

• Improved product and nano-dispersion stability

Summary:Properties of DocuSolv™ as Excipient

The Formulator’s First Choice

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Thank You

Questions?

www.solvay.com

Acknowledgements:

Eric Saly (Solvay)Eduardo Kamenetzky (Solvay)Alexandre Graet (Solvay)

Collaborations with Drs. Matthias Rischer, Wolfgang Mohr, Lena Kurz and AnsgarBögerhausen of Losan Pharma

novel docusate excipients for poorly soluble apis

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