Pharmaceutical Process Technology Poorly Water ... - TB Bio-Engineering/Pharmaceutical... ·...

technische universität dortmund

faculty of biochemical and chemical engineering

Pharmaceutical Process Technology Poorly Water Soluble Drugs

Prof. Dr. Markus Thommes Chair of Solids Process Engineering [email protected]

2 Chair of Solids Process Engineering

Poorly Water Soluble Drugs Biopharmaceutical Classification System (BCS)

Thommes 2015

G. Amidon, A Theoretical Basis for a Biopharmaceutic Drug Classification, Pharm Res 1995, 413-420.

H i g h L o w

High

I II particle size reduction, soluble salts, solid dispersions, self emulsifying systems, addition of surfactants, nano particles, cyclodextrine complexes, pH adjustments…

Low

III absorption enhancing excipients, efflux inhibitors, lipid filled capsules…

prodrugs, salt forms, cosolvents, solubilization by surfactants, nano particles, liposomes, lyophilization

SOLUBILITY


Poorly Water Soluble Drugs Low Aqueous Solubility

Lipinski’s Rule of Five (1997) > 5 H-bond donors > 10 H-bond acceptors > 500 g/mol > 5 LogP

low aqueous solubility frequently low bioavailability

Thommes 2015

C. A. Lipinski, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews, 2001, 3-25.

Emodepside, cs < 10mg/l (pH-dependent)

Carbamazepine cs= 130 mg/l

Itraconazole cs= 0.1 mg/l

Griseofulvine cs= 20 mg/l


Poorly Water Soluble Drugs Dissolution Process

Thommes 2015

∆𝑅𝐺 = ∆𝑅𝐻 − 𝑇𝑇𝑇 ∆𝑅𝐻 = ∆𝐿𝐻 = ∆𝐺𝐻 + ∆𝑠𝐻 + ΔDH

crystal gas

solution

ΔsH ΔLH

ΔGH

X++Y-

ΔDH

ΔLH Henderson-Hasselbalch

Gibbs Free Energy

• modification of pH • salt formation

Diclofenac (Sodium Salt) Quinine (HCl or Sulfate)


Poorly Water Soluble Drugs Lipid Formulations Non-Emulsifying (NEDDS) Self-Emulsifying (SEDDS) Self-Micro-Emulsifying (SMEDDS)

Thommes 2015

Rades, PolGerSym, 2012; Mistry, Int J Pharm Pharmkol Sci 2011

80

20

20

20

40

40

40

60

60

60

80

80

100

100 100 0

0

0 Lipid Tenside

o/w

w/o bicontin.

Water

Brand Name Drug Dosage

Form Manufacturer

Neoral Cyclosporine Soft gelatin capsule

Novartis

Norovir Ritonavir Soft gelatin capsule

Abbott laboratories

Fortovase Saquinavir Soft gelatin capsule

Hoffmann-La Roche

Agenerase Amprenavir Soft gelatin capsule

Glaxosmithkline

Solufen Ibuprofen Hard gelatin capsule

Sanofi - Aventis

Lipirex Fenofibrate Hard gelatin capsule

Sanofi - Aventis


Poorly Water Soluble Drugs Polymorphe, Pseudopolymorphe

Grzesiak, J.Pharm.Sci., 2003

XRPD-Pattern of Carbamazepine polymorphes

DSC-Thermograms of Carbamazepine polymor.

Carbamazepine

Thommes 2015


Poorly Water Soluble Drugs Particle Size Reduction

Nernst and Brunner

Hixson and Crowell

Ostwald and Freundlich

Calculated dissolution time of spherical griseofulvin crystals

Thommes 2015


Poorly Water Soluble Drugs Particle Size Reduction

Particle size distribution determined by laser diffraction

Dissolution profile in water from tablets (av ± CI, α = 0.05)

Plasma profiles of beagle dogs (av ± CI, α = 0.05)

Phase diagram of grisofulvin and mannitol

Thommes 2015


Poorly Water Soluble Drugs Nano Particles Preparation

Top Down Method • Ball milling

- milling of particles in suspension - stiff balls in micrometer size range

are mechanically agitated - amorphisation of the material

• High pressure homogenization - milling in suspension - fracture of material due to high shear

rates - stabilization of the suspension

required

Bottom Up Method (Precipitation) - using solvent and anti solvent - instantaneous mixing - scalability issues in manufacturing

Wacker, Nanocarriers for intravenous injection – A long hard road to the market, Int J Pharm 2013

Thommes 2015


Poorly Water Soluble Drugs Solid Dispersion

modified: Chiou, Riegelman, J. Pharm. Sci. 1971, p. 1281-1302; Leuner, Dressman, Eur. J. Pharm. Biopharm,2000 p. 47-60; Breitenbach, Eur. J. Pharm. Biopharm, 2002, p. 107-117

∆𝑅𝐺 = ∆𝑅𝐻 − 𝑇𝑇𝑇 Crystal Gas

Solution

ΔGH

ΔsH ΔLH ∆𝑅𝐻 = ∆𝐿𝐻 = ∆𝐺𝐻 + ∆𝑠𝐻

Drug

Carrier Extrudat – Solid Dispersion

crystalline amorphous crystalline/ amorphous

crystalline crystalline crystalline amorphous

crystalline/ amorphous amorphous crystalline crystalline molecularly dispersed

1 phase 2 phases

solid dispersions

solid solution

glassy solid solution

complex/ cocrystal

amorphous precipi-tation

eutectic solid crystal suspension

glass-suspension

DRUG

CARRIER

TERM

Thommes 2015


Poorly Water Soluble Drugs Preparation of Solid Dispersions Solvent Method

General • drug and carrier dissolved in

organic solvent • overcome the crystal lattice

energy • “rapid” evaporation of the

solvent Solvent Casting

• solution is casted on a liner (polymer film)

• evaporation of solvent by vacuum or temperature

Spray Drying • micrometer size droplets • spherical hollow particles

Stahl: Feuchtigkeit und Trocknen, Product information Büchi GmbH, Product information Erichson GmbH spray dryer, schematic drawing

Thommes 2015


Co-rotating twin screw extruder consisting of a 1) die, 2) heating device, 3) cooling device, 4) barrel and 5) screws

Poorly Water Soluble Drugs Preparation of Solid Dispersions - Fusion Method

General • drug and carrier are molten or

drug is dissolved in molten carrier

• overcome the crystal lattice energy

• “rapid” solidification Quench Cooling

• low viscous melts • pouring on cold metal surface or

into liquid nitrogen Hot Melt Extrusion

• high viscous melts • co-rotating twin screw extruder • granulation unit

M. Thommes, PhD Thesis, University of Duesseldorf, 2006, Bialleck, Rein, Eur. J. Pharm. Biopharm., 2011, p. 440-448

Thommes 2015


Poorly Water Soluble Drugs Process Development – Glassy Solid Solution

Mixing Temperature • determination by hot stage

microscopy or DSC • modeling e.g. PC-SAFT

Specific Feed Load • fill level of the screw during

extrusion • should be constant in scaling

Specific Mechanical Energy • mechanical energy applied to the

material • mainly transferred into heat

Paus et al., Molecular Pharmaceutics 12 (2015), pp. 2823ff

T

Polymer API

Amorphous demixing

(LLE)

𝒙𝑨𝑨𝑨𝑳(𝑪) 𝒙𝑨𝑨𝑨

𝑳(𝑨)

Analytical Sides of a Glass Solution Extrusion Process – Thommes – 04.12.15


Poorly Water Soluble Drugs Process Development - Glassy Solid Solution

General • drug molecularly dispersed in

amorphous carrier (polymer) • drug release determined by

dissolution kinetics of polymer • most common type of solid

dispersion

Manufacturing • solvent method (spray drying)

expensive – limited to thermal sensitive API

• fusion method (hot melt extrusion) – mixing/dissolving drug in polymer melt

Powder Blending

Hot Melt Extrusion

Cooling/ Grinding

Drug Carrier

Granules

Melting

Dissolving

Mixing {



Poorly Water Soluble Drugs Process Development - Glassy Solid Solution

simplified approach: considering the extruder just as mixer

Specific Feed Load • (dt. Durchsatzkennzahl) • characterizes the throughput

of the extruder

Material Temperature • determines the solubility of

the drug in the polymer • does not necessarily correlate to

barrel temperature • effected by shear rate of screw

scre

w s

peed

↑

feed

rate

↑

die opening ↑ shear elements ↑



Process Development Glassy Solid Solution – Specific Feed Load

SFLmin • lower limit for reliable

manufacturing • related to extruder size • ~ 2-10% of nominal throughput

and nominal rotation speed specific for extruder

SFLmax

• upper limit of manufacturing • depends on material density and

material flow • also related to screw geometry

(da/di) and rotation speed specific for formulation



Process Development Glassy Solid Solution – Material Properties

TGPolymer • glass transition temperature of

polymer • temperature range where the

polymer becomes plastically deformable

• no extrusion below this point determined by DSC, TMA

TMDrug

• melting point of the drug • often related to thermal

degradation – decrease of viscosity of the melt

hot stage microscopy, DSC




TDPolymer • degradation temperature of the

polymer • upper temperature limit for

manufacturing information provided by polymer

supplier

TDDrug • degradation temperature of the

drug • upper temperature limit for

pharmaceutical quality HPLC, GC, TGA, MS




TGFormulation • glass transition of the formulation • in glassy solid solution the drug

acts as plasticizer for the polymer – low glass transitions

• often correlated with physical stability of the formulation

determined by DSC, TMA

TMixing • temperature where defined

concentration of drug dissolves entirely in the polymer

• above this temperature glassy solid solution, below glass suspension

determined by DSC, hot stage microscopy



Torque Limit • mechanical limit of the extruder • relevant at high viscosity and

low screw speed • “at low speed the extruder has

not enough power”

Plasticization Limit • viscosity at the glass transition

too high for extrusion • decrease of viscosity by higher

temperatures determination by experiments

(related to formulation and equipment)

Process Development Glassy Solid Solution – Mechanical Limit



Process Development Glassy Solid Solution – Equipment Parameters

Specific Mechanical Energy • energy applied per gram material • transformation of mechanical to

thermal energy • desired: autogenic extrusion – no

heating of the material by barrel determination torque, motor power

Residence Time (Distribution) • dwell time distribution of an infinite

small volume in the extruder • related to dissolution and thermal

degradation determination by tracer experiments

Extrusion setup with torque sensor

Barrel Transmission Motor

Torque sensor



Process Development Glassy Solid Solution – Process Regions

Gray Region • below SFLmin: no reliable extrusion • above SFLmax: overload by feed

rate • left from torque limit: overload by

torque

Red Region • above TDDrug: not meaningful • below TMixing: wrong solid state

Orange Region

• suitable for extrusion process • high distance to TDDrug aimed




Green Region • desired region • reliable extrusion

A) Start Process Development

• barrel temperature between TMix and TDDrug

• medium screw speed ~ 100rpm • low feed rate 1800kg/h

equilibration takes some time

(15min) SME = 0.556kWh/kg RT10;50;90 = 226; 302; 451s

A




B) Increase Load of Barrel • step wise decrease of the screw

speed – waiting for equilibration • clogging of powder hopper or

maximum power consumption • screw speed: 75, 50, 40, 30rpm • clogging the hopper at 30rpm • 35rpm – stable process SME = 0.371kWh/kg RT10;50;90 = 211; 291; 469s

C) Autogenic Extrusion • turn of barrel heating and

cooling TMaterial = 143°C SME = 0.412kWh/kg RT10;50;90 = 257; 354; 572s

A

B

C

B

B

B D



Process Development Glassy Solid Solution – Process Regions D) Increase of Throughput

• simultaneous increase of screw seed and feed rate

• feed rate = 5.4kg/h • screw speed = 105rpm • TMaterial = 163°C SME = 0.298kWh/kg RT10;50;90 = 87; 116; 191s

E) Further Increase of Throughput • feed rate = 16.3kg/h • screw speed = 315rpm • TMaterial = 185°C SME = 0.238kWh/kg RT10;50;90 = 29; 41; 59s

A

B

C

B

B

B D E F



Process Development Glassy Solid Solution – Process Regions F) Sweet Spot

• feed rate = 16.3kg/h => 391kg/d • screw speed = 315rpm • TMaterial = 185°C SME = 0.238kWh/kg RT10;50;90 = 29; 41; 59s

Further Increase of Throughput • change of screw sequence

(lower staggering angle of kneading blocks – lower TMaterial)

• process is feed-limited scaling by constant SFL

A

B

C

B

B

B D E F

Screw Diameter [mm] 10 30 50 70 90

Throughput [kg/h] 2.2 60 280 762 1620

Throughput [kg/d] 53 1440 6720 18288 38880

Calculated Nominal Throughput (Eudragit EPO, Kollidon VA 64)



Processing of Solid Dispersion Tablet Formation

dissolution profiles in Soluplus extrudate, compressed to tablets (n=6; AV±CI)

Soluplus (polyvinyl caprolactam-polyvinyl acetat-polyethylen glycol graft copolymer)

gel formation of solid dispersion in water

0 30 60 90 120 150 180 210 240 270 3000

20

40

60

80

100

m m m

drug

relea

se [%

]time [min]

100-315µm 315-500µm 500-800µm

dissolution profiles in Soluplus extrudate containing carbamazepine using different particle sizes (n=6; AV±CI)

Reitz E., Pharm Ind 2013



Conclusion

Quick Test 1) Sate Lipinski’s rule of five. 2) How could nano particles be produced? 3) Name the manufacturing processes to produce glassy solid solutions. 4) Name the temperature boundaries for a glassy solid solution process. 5) Name different types of solid dispersions.

Engineering Thumb

A) How much energy could a screw extruder consume? B) What could be the minimal specific feed load of a hot melt extrusion? C) What could be the saturation concentration of griseofulvin and marble (dt. Marmor) in water? D) What could be the drug loading of a solid dispersion?

Thommes 2015

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