2. Design in Pharmaceutical Product Development

1

Design & Selection of Drug Substance

2

High Failure Rate

• For every 10,000 NCE’s in Discovery 10 enter pre-clinical development 5 enter human trials 1 is approved

• Interestingly….. Winning the lottery 1 in 5,200,000 A Royal Flush in Poker 1 in 650,000 Struck by lightning 1 in 600,000 Appear on the Tonight Show 1 in 490,000 Discovery to Market 1 in 10,000 A son who will play pro football 1 in 8000

3

Make, screen & push more compounds into the pipeline!

‘HITS’

DevelopabilityScreens

In Silico Screening

Optimisation

DRUGPRODUCT

Lead Compounds

Combinatorial Chemistry

High ThroughputScreening

4

Combinatorial Chemistry & HTS: Poor Solubility

Drug Discovery Before 1990

• lead compounds - drug like

• potency improved by adding lipophilic moieties

• low mol. weights circa.300

Drug Discovery After 1990• advent of HTS

• uses organic solvents to screen in vitro potency

• lead optimisation occurs by – increasing mol. weight – lipophilicity

540 % of compounds made each year are abandoned due to poor

solubility- Giovani Sala, Elan Pharma

Brick Dust !

hundreds of compounds evaluated in parallel using rapid, high throughput predictive assays

CombinatorialLibrary

Potency Selectivity Kinetics Tissue penetration Carcinogenicity Physicochemical

Properties

Drug candidate

Increase choice Improve selection

Preformulation and Developability Screening

6

Solubility: Double Edged Sword

• Relative difficulty in formulation design*

– poor permeability

– high first pass metabolism

– poor chemical stability

– low solubility

– instability in GI fluids

– high dosage

• More flexibility in altering physical chemistry then physiology

– absorption rate can vary from 0.001 - 0.05 min-1 i.e. x 50

– solubility can vary from 0.1 µg - 100 mg/ml i.e. x 1000,000

– target solubility is 1mg/ml (covers 1 mg to 500 mg oral dose)

7• Taken from a survey of formulation scientists

from 12 companies in Japan

least

most

GIT Physiology

• Potential for chemical degradation under different pH’s

• Changes in mucosal SA, presence of specific absorption windows

• Influence of endogenous secretion along the GI-tract

• Influence of gastric emptying, transit time and food dependency

• Influence of hydration state and water availability along GI-tract

• Pre-systemic availability – membrane/faecal binding & metabolism

8

Gastro Intestinal Tract conditions

• Absorbing surface area of the colon (~0.3m2) very small c.f. rest of GIT (120-200m2)• High viscosity of lumen contents can compromise drug diffusion and therefore absorption• Long residence times (up to 16 hrs)• Densely populated with microbial flora 9

Predicting good oral absorption

Increasing dose

Incr

easi

ng

per

mea

bil

ity

250 500 1000 10000 100000

Volume (ml) required to dissolve the dose5000

10

1

0.1

Pre

dic

ted

Pe

rme

ab

ility

in H

um

an

s (c

m/s

ec

x10-4

)

Class I

Good solubility andpermeability

Class IIIGood solubility,

poor permeability

Class IVPoor solubility and

permeability

Class IIa (dissolution rate limited)

Class IIb (solubility

limited)

Jejunal solubility (e.g. FaSSIF)

Poor solubility, good permeability

Good Difficult

Poor Very poor

Particle size reduction or other bio-enhancement required

Increasing solubility

Dose/solubility ratio

Butler & Dressman, JPharmSci. Vol 99, Issue 12, pp 4940–4954, Dec 2010

Physico-chemical methods for Boosting Oral Absorption*

• Use a Form with higher solubility

• more soluble polymorph

• more soluble salt

• amorphous c.f. crystalline form

• Formulate so drug is in solution

• Increase rate of dissolution

• particle size

11*many principles applicable for parenteral delivery

Use a form with higher solubility

12

Crystal Form

• Depending on crystallising conditions, actives may exhibit:

– different habits

– different polymorphs

– solvates (solubility: organic > non solvate > aqueous solvate)

• Polymorphs with lowest free energy (lowest solubility) tend to be more thermodynamically stable

– metastable (more soluble) form less soluble form

– smaller the difference in free energy the smaller the difference in solubility

– could we use metastable form for safety assessment?

13

0

5

10

15

20

25

0 6 12 18 24

100% B

50%A &50%B

100% A

Serum Levels: Chloramphenicol Palmitate

Effect of Polymorph Type

14

Crystal Form

Polymorphicform

Cmax

(g/ml)tmax

(hr)AUC

(g.h/ml)

I 44 3 226

II 85 2 590

III 80 3 576

15

Bioavailability of tolbutamide polymorphs in dogs

Amorphous forms• Amorphous forms afford better solubility & faster dissolution rates

c.f. crystalline forms– e.g. novobiocin, troglitazone

• Amorphous forms can transform to a more stable, but less soluble crystalline state

– tendency to transform is related to Tg & storage temp

– Tg > 80oC for amorphous solids to remain stable at RT

– for investigative studies low temperature storage to retain amorphous form is viable

– can stabilise by formulating with excipients of higher Tg

• PVP (Tg, 280oC) inhibits crystallisation of Indomethacin

• melt-extrusion with PVP to form granules or tablets 16

Granulator

Shaping Device

Tablets

PolymerExcipientDrug

Granulation

Pellets

Schematic view of Melt Extrusion

17

Plasma Profile data for SB-Compound

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0.0 4.0 8.0 12.0 16.0 20.0 24.0

Time (Hours)

Pla

sm

a C

on

cen

trati

on

(u

g/m

L)

Melt Extrusion

SuspensionMicronised Drug

18

pH adjustment & Salt Form

• Any drug moiety with a pKa between 3-11 can potentially be solubilised by pH modification

• Salt-Formation is an extension of pH adjustment. Most common forms are as follows:

– acidic drugs: sodium>potassium>calcium

– basic drugs: hydrochloride>sulphate>mesylate

>chloride>maleate>tartrate>citrate

• Salt-form requires agreement from all development parties– highly soluble form might be hygroscopic & unstable

choose the best ‘all-rounder’ 19

pH Solubility Profiles

• Intrinsic solubility (S0) region – pH range in which compound is completely unionized and has the lowest solubility.

• Ionized region – region around pKa of compound. At pKa are equal amounts of ionized and unionized forms of the compound in solution. For every pH unit change either side of the pKa gives a 10-fold change in amount of ionized drug in solution. Implications for lab measurements (pH control), & GI pH/ absorption. Compound precipitating in this region can be as free base or salt (depends upon the strength of solid-state interactions).

• pHmax – the region where compound has maximum solubility (equilibrium solid state form will be a salt i.e. completely ionized drug associated with oppositely charged counter-ions).

• Salt plateau – pH range in which the molecule is fully ionized and the salt solubility of the compound predominates. Solubility value is dependent upon strength of solid-state interactions with the counter-ion forming the salt. (Common ion effects & solvent can impact solubility.)

20

Weak Base

Solubility=S0(1+10(pKa-pH) )

S0=intrinsic, solubility of free acid/base

SO=0.528mg/mlpKa5.54

Classical pH-Solubility profile

S0=intrinsic, solubility of free acid/base

Salt Form

compound solubility in water (mg/ml)

RPR-127963 free base not detected

hydrochloride 3.9

mesylate 108

citrate 0.8

tartrate 0.9

sulphate 50

22

Aqueous solubilities of RPR-127963 salts

• Sulphate was progressed into development

• Could use a more soluble form for investigative studies?

Plasma Profiles for U-103017 in the Beagle Dog @ 10 mg/kg

0

20

40

60

80

100

120

140

160

0.0 2.0 4.0 6.0 8.0

Time (Hours)

Pla

sm

a C

on

cen

trati

on

(u

M)

Di-SodiumSalt

Free AcidSuspension

23

Formulate so drug is in solution

24

Solubilising Vehicles: organic solvents

Solvent Compounds

cremophor(polyoxymethylated castor oil)

miconazole, paciltaxel

dimethylacetamide tensoposide, busulfan

ethanol diazepam, phenytoin

glycerin epinephrine,idarubicin

PEG 300 and 400 lorazepam, etoposide

propylene glycol phenobarbital, hydralazine

sorbitol nicardine, triamcinolone

polysorbate 80 dexamethasone, docetaxel

25

Organic solvents used in commercial parenteral formulations

Solubilising Vehicles

Solvent/Cosolvent Issue

Polyethylene glycol Laxative, LMW residues

Propylene Glycol Dose limitation

Ethanol Effect of chronic dosing

Dimethyl Acetamide Irritation

Oily Vehicles Solubilising limitations

26

Complexation:CyclodextrinsEnhance the Drug’s Water Solubility

Increase Drug’s Aqueous Solution Stability

Improve Solubility & Dissolution: Improve Oral Bioavailability

Effective Delivery

Drug:CDComplex

Lipophilic Cavity

Hydrophilic Exterior

OH

CH2OH

HO

CHCH

1:1 Complex

Lipophilic

Drug

27

Plasma Profiles of Glibenclamide (3 mg dose) in dogs

0

100

200

300

400

500

600

700

0 4 8 12 16 20 24

Time (Hours)

Pla

sm

a C

on

cen

trati

on

(n

g/m

L)

Captisol Complex

Crystalline Material

28

Complexation:Cyclodextrins

Species

i/v AUC

(mgh/ml)

cyclodextrin AUC

(mgh/ml)

m/cellulose suspension

AUC (mgh/ml)

mouse 137.0 143.0 63.7

rat 89.4 58.6 43.0

dog 89.4 58.6 43.0

monkey 115.0 59.4 15.9

29

Bioavailability of Sch-56952 (azole anti-fungal) in animals

Increase rate of dissolution

30

Solubility & Dissolution Rate

Dissolution Rate

D.Ae.Cs R

Where

D = Diffusion Coefficient

Ae = Effective Surface Area

Cs = Saturation Solubility

R = Thickness of Diffusion Layer

Surface Area as a function of Particle Size

-1.0E+5

0.0E+0

1.0E+5

2.0E+5

3.0E+5

4.0E+5

5.0E+5

6.0E+5

7.0E+5

8.0E+5

0.01 0.1 1 10 100

Particle diameter (um)

Spe

cifi

c S

urfa

ce A

rea

(cm2 /c

m3 )

31

Danazol Bioavailability (Dog)

32

0

0.5

1

1.5

2

2.5

3

3.5

0 5 10 15 20 25 30

Time (hrs)

Dan

azo

l (u

g/m

l p

lasm

a)

Conventional Suspension (n=5)

Nanoparticulate Dispersion (n=5)

Cyclodextrin Complex (n=5)

The NanoCrystal™ Advantage

• Rapamune (Wyeth)– Sirolimus – Immunosuppressant– was available as a sachet &

reconstituted suspension– required storage in a fridge

• Using Nanocrystals– possible to supply a solid oral

tablet formulation– more stable– more convenient

33

Comparison of U-103017 Formulations @ 10 mg/kg in the Beagle Dog

050

100150200250300350400450500

Sol

utio

ns

Di-N

a S

alt

Am

orph

ous

Sus

p

Bul

k D

rug

caps

ule

Sus

pens

ion

Mill

ed S

uspe

nsio

n

Sub

-Mic

ron

Sus

pens

ion

HP

MC

-P D

ispe

rsio

n

PV

P D

ispe

rsio

n

PE

G 3

350

Sol

id

Gel

ucire

Sol

id

Sal

t Spr

ay D

ried

40%

Sal

t Bea

d C

ap

AU

C (

uM

.hr)

Reference 14Reference 1434

35

Regardless of route a drug needs to dissolve first!

Take Home Message

Formulating the drug substance into a Product

36

Requirements of a Dosage Form

• Contains an Accurate Dose.

• Makes drug available for absorption (oral dosage).

• Is stable (retains quality).

• Convenient to take or administer.

• Is produced economically by an acceptable process.

37

Effect on Drug

“Know your Dosage Form”

Optimise Levelsof Excipients

Addition of other materialsEngineering Technologies

Physical Modifications

Compensate forDeficiencies

“Know your Drug”

Formulation Development

38

Functions of Excipients

• Compensate for deficiencies in the drug

• Aid manufacture of the dosage form

• Quality assurance and maintenance

• Identity, patient acceptability– colour– taste

• “Target” the drug to site of activity– absorption– site-specific delivery

39

Standards for Excipients

• Must not interact (adversely) with the drug

• Must not compromise safety or tolerance

• Function in the manner intended

40

Factors affecting performance of oral dosage forms

• particle size of active

• granulation– granulating agents

– mode of granulation

• lubricant– type

– degree of mixing

• compression force

• film coat

41

All need to be evaluated: CMC section of regulatory submission

Clinical Studies

42

Phase I absorption, metabolism, tolerance (volunteers)

Phase 2A “does the drug work” ? (efficacy)

“ 2B dose/dose regimen

Phase III “how good is it”

Phase IV post-marketing studies

Ideal that the same formulation is used at all stages

Dosage Forms for Clinical Programmes

43

Phase One Flexibility of Dose- powder in bottle- capsule- tablet

Phase Two Range of Doses in “look-alike” units- tablet- capsule

Phase Three Formulation for Marketing

FDA will not consider tablets & capsules as bioequivalent!

Tablets more popular than capsules (smaller & more stable)

What does a dose look like?

44

Preclinical stage Phase 1 stagePhase 2 stage

Phase 2/3Phase 4 stages

Why do Formulations Change ?

• Technical problems

• Need to incorporate different doses

• Nature of clinical programmes

45

Formulation and the Stock Market

46

“To Merck’s dismay, Monsanto completed its clinical studies first. Among the reasons was a dosage glitch at Merck. The company found that, instead of 1000mg, the proper dose was 12.5-25mg. The pills that resulted were so tiny that Merck was afraid that Arthritis patients wouldn’t be able to pick them up.

It enlarged them with edible filler but that caused another problem. The fiber turned out to slow the drug’s absorption. Three months were lost while researchers worked to fix this”

Wall Street Journal January 10th 2001

Impact of changing dose!

Very difficult to accommodate large changes in dose, as it

will influence processing & manufacturing on scale-up

47