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2. Design in Pharmaceutical Product Development. Design & Selection of Drug Substance. 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

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high failure rate
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

Make, screen & push more compounds into the pipeline!




High Throughput



In Silico


Lead Compounds






combinatorial chemistry hts poor solubility
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

BrickDust !

40 % of compounds made each year are abandoned due to poor solubility-Giovani Sala, Elan Pharma


Preformulation and Developability Screening

  • Potency
  • Selectivity
  • Kinetics
  • Tissue penetration
  • Carcinogenicity
  • Physicochemical Properties



Drug candidate

Increase choice

Improve selection

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

solubility double edged sword



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)
  • Taken from a survey of formulation scientists
  • from 12 companies in Japan
git physiology
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
gastro intestinal tract conditions
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
predicting good oral absorption
Predicting good oral absorption

Volume (ml) required to dissolve the dose

Dose/solubility ratio







Increasing permeability

Jejunal solubility (e.g.



Class I

Class IIa

Class IIb







rate limited)

Good solubility and


Poor solubility, good permeability

Particle size reduction or other bio-enhancement required

Predicted Permeability in Humans (cm/sec x10-4)


Class IV

Class III

Poor solubility and permeability

Good solubility,

poor permeability

Very poor



Increasing solubility

Increasing dose

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

physico chemical methods for boosting oral absorption
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

*many principles applicable for parenteral delivery

crystal form
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?
crystal form1
Crystal Form

Bioavailability of tolbutamide polymorphs in dogs

amorphous forms
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

Schematic view of Melt Extrusion




Shaping Device





ph adjustment salt form
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


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

choose the best ‘all-rounder’

ph solubility profiles
pH Solubility Profiles

Weak Base

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

  • 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.)




S0=intrinsic, solubility of free acid/base

classical ph solubility profile
Classical pH-Solubility profile

S0=intrinsic, solubility of free acid/base

salt form
Salt Form

Aqueous solubilities of RPR-127963 salts

  • Sulphate was progressed into development
  • Could use a more soluble form for investigative studies?
solubilising vehicles organic solvents
Solubilising Vehicles: organic solvents

Organic solvents used in commercial parenteral formulations

solubilising vehicles
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


Hydrophilic Exterior






Lipophilic Cavity

  • Complexation:Cyclodextrins
    • Enhance the Drug’s Water Solubility
    • Increase Drug’s Aqueous Solution Stability
    • Improve Solubility & Dissolution: Improve Oral Bioavailability
    • Effective Delivery





1:1 Complex

complexation cyclodextrins

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

solubility dissolution rate
Solubility & Dissolution Rate

Dissolution Rate




D = Diffusion Coefficient

Ae = Effective Surface Area

Cs = Saturation Solubility

R = Thickness of Diffusion Layer

the nanocrystal advantage
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

Take Home Message

Regardless of route a drug needs to dissolve first!

requirements of a dosage form
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.
formulation development

“Know your Drug”

Compensate for


Addition of other materials

Engineering Technologies Physical Modifications

Optimise Levels

of Excipients

Effect on Drug

“Know your Dosage Form”

Formulation Development
functions of excipients
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
standards for excipients
Standards for Excipients
  • Must not interact (adversely) with the drug
  • Must not compromise safety or tolerance
  • Function in the manner intended
factors affecting performance of oral dosage forms
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

All need to be evaluated: CMC section of regulatory submission

clinical studies

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

Clinical Studies
dosage forms for clinical programmes
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)

Dosage Forms for Clinical Programmes
what does a dose look like
What does a dose look like?

Phase 2/3

Phase 4 stages

Preclinical stage

Phase 1 stage

Phase 2 stage

why do formulations change
Why do Formulations Change ?
  • Technical problems
  • Need to incorporate different doses
  • Nature of clinical programmes
formulation and the stock market
Formulation and the Stock Market

“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
Impact of changing dose!

Very difficult to accommodate large changes in dose, as it

will influence processing & manufacturing on scale-up