Direct compression technology

ROQUETTE outstanding range of Direct Compression excipients

Philippe Lefvre Global Pharmaceutical Applications Coordinator November, 2012

Philippe Lefvre

Direct compression technology with ROQUETTE DC excipients

Agenda
Direct compression requirements API & excipients powder properties Formulation ROQUETTE range of DC excipients Mannitol PEARLITOL SD: the ideal DC excipient NEOSORB P300DC & P150DC, SWEETPEARL P300DC & XYLISORB DC Indicative formulation guidelines StarLac

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

Direct compression: a simple process

Weighing Blending Wetting Granulating Drying Calibration Lubrication Tabletting

Weighing

Blending

Lubricating

Tabletting

4 steps !

Easy!
Philippe Lefvre 2012

The DC is born!
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ROQUETTE range of excipients for direct compression

The advantages of Direct Compression Technology

API stability by avoiding heat and humidity Good disintegration, especially for dispersible tablets/ODT Better mouth-feeling (chewable tablets, suckable tablets) Less process steps for manufacture and quality control High production rate Cost saving (equipments, energy, process control, staff)

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

The basic requirements of Direct Compression

Pharmaceutical Technology,2005
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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Direct compression excipients Optimal physical properties

Powders: granules, no crystal shape Particle size: mean diameter>100m

(fine powder amount should be limited and controlled)

Tap density: 0.4-0.7g/ml

(to optimize mixing and tablet press die filling)

Configuration (Aspect ratio<1.5 For an homogeneous blend, same particle size and density than API For water sensible API or tablet, use a not hygroscopic excipient as mannitol PEARLITOL
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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Direct compression _ API ratio

API 3%, need for an adapted mixing process

good flowability excipient high effective mixing equipment gradient mixing, sieving if necessary dissolve APIthen spray the solution to particle, fluidized bed tech

3% API10%: easy process

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

Direct compression - API ratio

10% API30%: feasibility depending on API physical properties API 30%: feasibility only with compactable API
APIs flowability and compactibility: DC grade API; re-crystallization; fluidized bed granulation; dry granulation

Whatever API ratios, the mixing process is essential

Perfectly homogenous blend after mixing steps Determination of the optimum mixing time with the mixing equipment used
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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ROQUETTE offers an outstanding range of DC excipients

mannitol: PEARLITOL DC & SD, PEARLITOL FLASH sorbitol: NEOSORB P60W, NEOSORB P150DC, NEOSORB P300DC STARLAC maltitol: SWEETPEARL P300DC xylitol: XYLISORB 100DC, 200DC Partially pregelatinised starch : LYCATAB C starch CaCO3 compound: LYCATAB Mineral -cyclodextrin: KLEPTOSE DC
ROQUETTE has today developed a full range of DC polyols, enabling customer to move from granulation to direct compression
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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ROQUETTE offers an outstanding range of DC excipients But how to choose?

Important offer of DC excipients which are all different Key Points:
Know perfectly the DC excipients properties Identify the API and formulation requirements

For unstable and water sensible drug, the ideal excipients: Mannitol PEARLITOL SD, DC or Flash
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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PEARLITOL SD & DC range

PEARLITOL SD and DC:
Pure mannitol excipients For direct compression PEARLITOL 200SD, PEARLITOL 100SD PEARLITOL 300DC, 400DC, 500DC
(Number = particle size)

PEARLITOL FLASH:
Compound composed mainly of mannitol with a small proportion of starch added Ideal excipient for Orally Dispersible Tablets Formulation
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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PEARLITOL SD & DC range

A range of particle sizes adapted to the diversity of drug particle sizes Highest particle sizes required by specific technologies (as coated micro granules) Corresponding to the majority of drugs requirements (as particle size), PEARLITOL 200SD is by far the most used
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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PEARLITOL 200SD: the ideal excipient

Benefits of using PEARLITOL 200SD in place of other DC excipients:
Easy and cost effective manufacturing process: Direct Compression High tablets stability High drug bioavailability High versatility: all type of tablets

PEARLITOL 200SD is the only excipient to combine all these properties

Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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PEARLITOL 200 SD: the stability of a pure mannitol

Mannitol: an exceptionally stable excipient
Not hygroscopic No unstable crystalline forms No amorphous mannitol No water of crystallization And soluble

Mannitol is the only excipient being not hygroscopic and soluble (opposite properties)

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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PEARLITOL 200 SD: the stability of a pure mannitol

Influence of Temperature on Hygroscopicity of Mannitol

10 9 Percen tag e o f w ater in th e p ro d u ct at eq u ilib riu m 8 7 6 5 4 3 2 1 0 0 10 20 30 40 50 60 70 80 90 100 Relative Humidity (%)

40C 30C 20C

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ROQUETTE range of excipients for direct compression

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PEARLITOL 200 SD: access to bioavailability

Mannitol is soluble (15.4 g/100 ml @ RT) Note that exceptional character of mannitol is to be simultaneously not hygroscopic and soluble PEARLITOL 200SD behavior in water is favorable to the action of superdisintegrant 1. Tablet disintegration 2. PEARLITOL dissolution Concretely, fast tablet disintegration and mannitol dissolution improve the drug dissolution and then the drug bioavailability 3. Drug dissolution 4. Drug bioavailability
Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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PEARLITOL 200 SD access to a simple & cost effective process

PEARLITOL 200SD: Free-flowing Highly compactable Simple and cost effective manufacturing process: direct compression High versatility Sweet, slight cooling effect Swallowable, chewable, orally dispersible, effervescent, suckable tablets
PEARLITOL P 200SD SEM View

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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PEARLITOL 200 SD access to a simple & cost effective process

MANNITOL COMPACTIBILITY (10mm diameter flat tablets)
320 280 240 Tablet hardness (N) 200 160 120
PEARLITOL 200SD

80 40 0 0 5 10 15 Compression Force (kN)

PEARLITOL 25C + 10% LYCATAB DSH PEARLITOL 50C + 10% LYCATAB DSH PEARLITOL 160C + 10% LYCATAB DSH

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PEARLITOL 200SD: to move from wet granulation to direct compression

Philippe Lefvre 2012 ROQUETTE range of excipients for direct compression
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Benefits of PEARLITOL 200SD: Wrap-up PEARLITOL 200SD an ideal excipient for pharmaceutical and nutraceutical tablets:
Unstable or water sensitive API Unstable or water sensitive tablets As effervescent tablets Fast disintegrating tablets Orally dispersible tablets all the type of tablets

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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How to select the appropriate PEARLITOL?

To formulate water sensible or unstable API or tablet: PEARLITOL mannitol
TABLET TYPE SUCKABLE SWALLOWABLE CHEWABLE ORODISPERSIBLE EFFERVESCENT MICROGRANULES API or tablet stability concern PEARLITOL 100 SD PEARLITOL 200 SD PEARLITOL 200 SD PEARLITOL 200 SD PEARLITOL FLASH PEARLITOL 200 SD PEARLITOL 400 DC

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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INDICATIVE FORMULATION GUIDELINES

Mannitol Sorbitol
NEOSORB P20/60DC NEOSORB P300DC, P150DC

Maltitol

Xylitol

sachet Soft chews Chewable

PEARLITOL SD, DC

SWEETPEARL P300DC SWEETPEARL P300DC

XYLISORB DC XYLISORB DC

PEARLITOL SD, DC NEOSORB P20/60DC NEOSORB P60W NEOSORB P20/60DC NEOSORB P60W NEOSORB P300DC, P150DC NEOSORB P20/60DC NEOSORB P60W NEOSORB P20/60DC NEOSORB P60W NEOSORB P300DC, P150DC

PEARLITOL SD, DC

SWEETPEARL P300DC

XYLISORB DC

PEARLITOL SD, DC

Suckable Swallowable Effervescent Fast dissolving

Philippe Lefvre 2012
PEARLITOL SD, DC

PEARLITOL SD, DC

SWEETPEARL P300DC

PEARLITOL Flash

ROQUETTE range of excipients for direct compression

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ROQUETTE outstanding DC excipients range: wrap-up

ROQUETTE DC excipients range
A solution for all DC formulations For unstable and stable API For all types of tablets And dry compaction, sachets, hard gelatin capsules filling To move from wet granulation to direct compression New DC polyols for access to new textures (SweetPearl P300DC, XYLISORB DC)
Sachets Swallowable Soft chews

Textures Effervescent Chewable

Suckable

Fast dissolving

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Solutions to common tablets production problems

Philippe Lefvre

Solutions to common tablet production problems Sticking to punches

Amount of magnesium stearate Is Magnesium stearate well mixed ? Too high room humidity: Is it controlled? Powders having adsorbed water: to be dried before tabletting Quality of punches Melting of the API Too low compression force

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Solutions to common tablet production problems No homogeneous mix or tablets

API and excipients having too different: Density Particle size Particle shape Poor flowability Poor compatibility Tablet machine feeling Forced feeding device? Speed of the force feeding device? Effectiveness of the mixing equipment A solution may be dry-granulation of API

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Solutions to common tablet production problems

Static electricity which cause aggregation

Too low environment humidity API or excipients overdrying Antistatic excipients: Talcum powder, Powder silica gel, Sodium dodecyl sulfate etc Drain off static charge Equipment grounding

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Solutions to common tablet production problems

Capping
Too low compactibility Too dry powder mixture Too high compression force Tablet shape Too convex tablets Gap between punches and die Too high tabletting speed Capping is mainly due to air entrapped in tablets during tabletting (deficient air exhaust) Pre-compression reduces dramatically capping

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Advantages and drawbacks of the main direct compression excipients

Philippe Lefvre

Spray dried lactose

Advantages
Good compactibility Low hygroscopicity Huge experience

Drawbacks
Animal original (BSE) Lactose intolerance Reducing sugar (Maillard reaction )

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Microcrystalline cellulose (MCC)

Advantages
High compactibility Efficient at low dosage Many grades available

Drawbacks
High water content (7.0) Easy to catch water Bad taste (Sand feeling ) Sensitive to magnesium stearate

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ROQUETTE range of excipients for direct compression

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Dibasic Calcium Phosphate (DCP)

Advantages
Good compactibility Non hygroscopic Calcium source

Drawbacks
Insoluble Alkaline surface

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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Partially pregelatinized starch : LYCATAB C

Advantages
Fast disintegration Self lubricating

Drawbacks
Hygroscopicity Sensitive to magnesium stearate Water content (about 8%)

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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StarLac (co-processed lactose and starch)

Advantages
Good compactibility Fast disintegration Easy to lubricate

Drawbacks
Animal original (BSE) Lactose intolerance Reducing sugar(maillard reaction )

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ROQUETTE range of excipients for direct compression

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NEOSORB P60W/ P100T NEOSORB P300DC

Advantages
Very good compactibility Sweet, cooling effect Very soluble Cost saving

Drawbacks
Slightly hygroscopic

NEOSORB P300DC is a new grade with a high specific surface (high oil adsorption)

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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PEARLITOL SD/DC
Advantages
Non hygroscopic Stability versus drug Quick disintergration (SD) High compactibility Free flowing soluble Sweet, slight cooling effect

Drawbacks
Generally high Magnesium stearate

?
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Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

PEARLITOL Flash
Advantages
Fast disintegration Easy to lubricate good compactibility Good mouthfeel Avoid patent issue

Drawbacks
USA DMF, no pharma regulation in China

Philippe Lefvre 2012

ROQUETTE range of excipients for direct compression

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