2. Design in Product Development

and Choice of Formulation

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 than 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 salt

• more soluble polymorph

• 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

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 15

Granulator

Shaping Device

Tablets

PolymerExcipientDrug

Granulation

Pellets

Schematic view of Melt Extrusion

16

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

17

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’ 18

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.)

19

Weak Base

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

S0=intrinsic, solubility of free acid/base

S0=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

21

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

22

Formulate so drug is in solution

23

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

24

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

25

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

26

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

27

Increase rate of dissolution

28

Solubility & Dissolution Rate

Dissolution Rate

D.Ae.Cs RWhere

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)S

peci

fic

Sur

face

Are

a (c

m2 /cm

3 )

29

Danazol Bioavailability (Dog)

30

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)

31

Take Home Message

Biology occurs in aqueous solution

Regardless of route a drug needs to dissolve first!

Modified Release Technologies

Terminology Definition (USP)

Controlled(including sustained/ prolonged release)

A Controlled Release (CR) dosage form is one in which the drug is released at a constant rate and therefore produces blood drug levels which remain invariant with time

Extended release An Extended Release (ER) dosage form allows a two-fold reduction in the frequency of dosing or increase in patient compliance or therapeutic performance

Modified release A Modified Release (MR) dosage form is one in which the drug release characteristics and/or location of release are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms

NB: Ph. Eur. uses extended release as denominator rather than modified release32

Technical argument

• How does MR drug delivery modulation add value?

• Reduced dosing frequency, thus promote patient compliance

• Reduced potential for side-effects (lessen peak/trough ratio)

• Customised profile, link drug level to efficacy performance

• Targeted delivery to specific GI regions for improved “delivery” opportunities

33

Drug properties

Ideal Challenging

Dose 10-250mg <10mg potential homogeneity issues>250mg payload and physical dosage size issues

Dose/solubility ratio*

1-100ml 100-1000ml challenging may need solubilisation>1000ml practically impossible

Permeability Abs > 70%Rat Ka> 0.01min-1

(Papps>15cm/s)

Papps 5-15cm/s absorption unpredictable

Papps < 5cm/s practically impossible

Stability 48hr in gut content @ 37°C

Interpretation can be complex – many facets to stability i.e., physical (binding, adsorption) and chemical

* Dose/solubility ratio calculated using the highest dose and lowest solubility in the pH range of 1 to 7.5.

34

Other considerations

Ideal Challenging

Plasma half-life 2 – 8 hr < 2hr high dependency on delivery rate to maintain steady state concentration>>10hr may not require MR delivery

Presystemic/first passmetabolism

No pre-systemic/low

1st pass metabolism

Pre-systemic drug loss increases overall dose requirements. CYP3A4 substrate introduces dose-dependent metabolism

Efflux and dose linearity BA/BA ratio < 1.8 fold

Dose linear

Efflux issues difficult to handle if dominant over therapeutic dose range

Therapeutic window > 4-fold < 4-fold challenging, reliant on very precise control of drug plasma level

35

Modes of Oral Modified Drug Delivery

• Most popular systems classified as follows: Osmotic pumps: Oros Swellable systems: HPMC matrix, Geomatrix etc Erosion controlled systems: Egalet

• Major issues still revolve around Choice of a suitable animal model Poor understanding of PK/PD relationships Chronotherapeutics Polypharmacy

What is the ideal in vivo release profile?

36

Osmotic pump systems

Cross-section of typical oral therapeutic system (OROS)

Delivery orifice

Drug solution

Semipermeable membrane

Delivery orifice

Drug compartment

Osmotic corecontaining activesubstance

WaterOsmotic propellant Flexible partition

37

Process complexity

• Process complex involving multiple steps• Bi-layer compression requires good control• Coating critical to meet dissolution target

Granulation Mill Blend and lubricate

Bi-layer tabletting

Coating Drilling

Granulation

DRUG LAYER

SWELLER LAYER

Mill Blend and lubricate

38

Chronotherapy

• Covera-24 was the first oral MR product approved for chronotherapeutic treatment for angina & hypertension

• Dose at night & release starts between 0200 - 0300 & counters the surge in blood pressure between 0400 - 0500

• Constant release continues to cover events during the day

39

Product Development Design Case Study

40

Case StudyProduct Line extension

• Your company markets an oral product for migraine – you are the PLE department and the commercial team have asked you to design a faster acting product.

• The product development team is asked to ‘brainstorm’ options for this development

• You have 20 minutes to discuss before feeding back your best concept to the Product Development Board

What do you need to know about the patient population?

What do you need to know about the disease?

What do you need to know about the properties of the drug?

What formulation technology will you use?41

Formulating the drug substance into a Product

42

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.

43

Effect on Drug

“Know your Dosage Form”

Optimise Levelsof Excipients

Addition of other materialsEngineering Technologies

Physical Modifications

Compensate forDeficiencies

Meet patient needs

“Know your Drug & Patient”

Formulation Development

44

Functions of Excipients

• Aid function of the dosage form• 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

45

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

46

All need to be evaluated: CMC section of regulatory submission

Dosage Forms for Clinical Programmes

47

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?

48

Preclinical stage Phase 1 stagePhase 2 stage

Phase 2/3Phase 4 stages

Why do Formulations Change ?

• Technical problems

• Different doses

• Nature of clinical programmes

49

Formulation and the Stock Market

50

“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

51