API and Dosage

Development
W I T H D A LT O N
Peter Pekos

[COMPANY VISION]
"To make the impossible possible. Dalton Pharma Services uses its scientific
and pharmaceutical expertise to bring customer ideas to life. We develop their
new drug products, optimize the synthesis of therapeutic candidates, and
manufacture them at the highest level of quality."

[SERVICES]
Contract Research
Custom Synthesis
Medicinal and Flow Chemistry
API Process Development Formulation
Development
cGMP API Manufacturing
cGMP Sterile Filling
Analytical and Microbiology Services

FDA inspected, HC approved, & MRA with EMA

 API Form Development

API Definition
Active pharmaceutical ingredient (API) – the substance(s) in pharmaceutical drugs that
is/are responsible for the beneficial health effects experienced by consumers. (1)

API Selection
Key factors that drive API selection (2):
Crystallinity:
Influences the dissolution rate and
transport characteristics of the
drug (3) Polymorphism:
The ability of a drug substance to
Solubility: take on more than one form/
The ability of a solute to dissolve in crystalline phase. Influences drug
solvent. Influences desired dissolution and drug stability (i.e.,
concentration and drug premature degradation) (4)
absorption (6)
Density:
Influences flow properties and
Stability: compressibility (5)
Influenced by moisture, excipients,
temperature, pH, oxygen, light (7) Particle size distribution:
Influences the ability of the drug to
Density: cross blood barriers, enter cells,
Influences flow properties and and absorbed by the human body
compressibility (5) (2)

The development stage and needs

API & CTD

Note: In any clinical application or new
drug submission the 1) description of
manufacturing (including flowcharts) is
required along with 2) physiochemical
characteristics (melting point, boiling
point, denaturation temperature,
solubility) (2.3.S.2, 2.3.S.3 and 2.3.P.3) (4)

Once the API form is determined, the

dosage form must be selected.
 Dosage Form Development

Formulation Drug Product Drug Product

Preformulation
Development Manufacturing Release

Preformulation Studies

Microscopic examination: Indicates particle size, size range, and crystal

structure
Heat of vaporization: Important for aerosol dosage forms and medication
delivery systems
Melting point depression: Helps determines purity
The phase rule: Indicates the drugs pressure, volume, and temperature in
thermodynamic equilibrium
Particle size: Influences the dissolution rate, bioavailability, content uniformity,
texture, and stability of your drug
Polymorphism: Influences melting point, solubility, bioavailability, and stability
Solubility: Required for therapeutic efficacy; Influenced by pH and particle size
Dissolution: Determines the time it takes for your drug to dissolve at the
absorption site; Influenced by the compaction of a drug. Compaction involves
two distinct stages (4):
Compression: initial particle re-arrangement under relatively lower
compaction pressure
Consolidation: material deformation at higher compaction pressure to form
inter-particulate bonds leading to the formation of compact mass. Material
deformation may be of three types – plastic, elastic and brittle fracture:
Plastic materials deform under pressure and do not regain their original
state after removal of compaction pressure
Elastic materials regain their original form after removal of compaction
pressure
Brittle materials break down into smaller particles under compaction
pressure
Membrane permeability: Influenced by particle size
Partition coefficient: Determines the ratio of the concentration of the drug
substance in one phase to the concentration in a second phase
pka/ dissociation constants: Dissociation or ionization is influenced by the pH
and influences the absorption, distribution, and elimination of your drug

Factors to consider when deciding your drug’s dosage form (8)

Functionality (absorption, Costs
bioavailability, stability) Marketing preferences
Suitability of ingredients (chemical, Target population (age, nature of
form, physical, pH, solubility) disease or illness)
Availability of ingredients/excipients Previous preclinical/ clinical data
 Dosage Form Development

Formulation Development
Various formulations are developed and examined for desired features and
critical quality attributes (CQA). According to ICH Q8 R2, a CQA is a “physical,
chemical, microbiological or biological properties which should be required
within the certain range or limit to confirm the predefined quality standard
product.” (9) The formulation that best meets the target product profile is
selected to be its master formula.

Formulation Testing
Stability studies to conduct when deciding dosage form (10)

pH studies Elevated temperature High humidity studies

studies

Photolytic studies Oxidation studies Hydrolysis

Formulation Options
There are a variety of dosage forms to choose from. Dosage forms are classified
based on the (10)
1) Physical state of the ingredient
Solid (tablets, capsules, powders, films, chewing gum, pellets, lozenges)
Liquid (syrups, injections, emulsion, solutions, suspensions, colloids,
liposomes, ophthalmic, oral, nasal)
Semisolid (gels, creams, ointments, lotions)
Gas (aerosols, inhalers, nebulizers)
2) Or the route of administration (ROA)
Enteral (oral, buccal, sublingual and rectal)
Topical (transdermal, ophthalmic, gels, creams, ointments, lotions)
Parenteral (intravenous, and intramuscular, subcutaneous injectables)
Inhaled (oral, nasal)

Offered at Dalton
 Dosage Forms (11), (12), (13)

Solids Tablets, Capsules

Pros 2
DATA VS Challenges
DATA 3

Formulated to give an exact dose Risk of choking and chewing

High level of consumer Compatibility with food/drink
acceptability/compliance/ May need taste masking
convenience requirements
Generally masks taste and odor of Difficult to adjust an exact dose
ingredients Impossible for unconscious
Good physical and chemical patients to consume
stability
Can be formulated for immediate
or controlled release
Economical to produce
Can be coated. This protects the
drug substance from degradation
by atmospheric oxygen, humidity,
or gastric acid
Various form options for tablets:
soft (chewable), effervescent,
lozenge (pastille), multi-layered,
and buccal/sublingual

Topicals Transdermal, Gels, Creams, Ointments, Lotions

DATA
Pros 2 VS DATA 3
Challenges

Painless and easy administration Unintended systemic

Sustained drug delivery absorption/toxicity risk in
neonate
Local skin irritation
Deliberate removal or patches
(consumer noncompliance)
Sterile Liquids Solutions, Suspensions, Colloids, Liposomes

Pros 2
DATA VS Challenges
DATA 3

Allows for dose adjustments Difficult to mask bad taste or

Easy to swallow odors of ingredients
Better bioavailability than solid May require a preservative
dosage forms system to prevent microbial
Acceptability from term birth growth and improve stability
Options for different doses and Potential for dosage inaccuracy
modified release Inconvenient to travel with
Solutions Potential sensitivity to oxygen or
Provides clear liquid dosage forms light
of substances through a liquid May be insoluble or chemically
preparation contains more than unsuitable in the presence of
one chemical substance water
homogeneously dissolved in a Suspensions require shaking or
liquid solvent or mixture of stirring of the liquid preparation
mutually miscible solvents (12) because it is not completely
Colloids dissolved in the desired vehicle
Expand circulatory volume
Liposomes
Permits a cell membrane drug
delivery vehicle that protects
drugs against chemical, enzyme,
and immunological breakdown
Emulsions
Allows for a mixture of two liquids
that would not normally mix
(immiscible liquids)

Sterile Liquid Ophthalmic, oral, nasal

Pros 2
DATA VS Challenges
DATA 3

Good nasal transmucosal Irritation of the mucous-

bioavailability Ineffective in abundant secretion
Avoidance of hepatic first pass Increased deposition in
metabolism upper/central airways
Powders Sterile and non-sterile powder filling

Pros 2
DATA VS Challenges
DATA 3

Allows for dose adjustments Must be mixed with a liquid-

Easier to swallow Difficult to mask bad taste or
Better bioavailability than solid odors of ingredients
dosage forms Not compatible with hygroscopic,
Can handle large dosing of oxidizing, and deliquescent
materials materials
Economical to produce Potential for dosage inaccuracy
Allows for multi-dose preparations Inconvenient to travel with
consisting of solid, loose, dry
particles of varying degrees of
fineness

Injectables Intravenous, intramuscular, subcutaneous injectables

Pros 2
DATA VS Challenges
DATA 3

Main route for neonates and Potential for infection

emergency cases Electrolyte imbalance
Sustained release preparation Inappropriate dilutants
Provides placement of a drug Lag-volume effects in IV line-
directly in the bloodstream or Needle puncture pain/phobia
body tissues Potential for plastic migration into
drug
Lyophilized formulations
Pros 2
DATA VS Challenges
DATA 3

Reduces biological and chemical Costly equipment

reactions at the designated Increases handling and
storage temperature through processing time
sublimation and desorption while
in the frozen state

Inhalants
Pros 2
DATA VS Challenges
DATA 3

Provides optimal drug action Irritant effects on airways

through inhalation therapy Additional work for delivery
system
 Regulatory

Australia
Drugs that meet the orphan criteria are eligible for
orphan drug designations (regulation 16J of the
Therapeutic Goods Regulations 1990).
In addition to standard orphan drug designation, drugs
can seek a pathway for orphan designation for new
dosage form. Eligibility for new dosage form medicines is
intended to provide an incentive to sponsors to register
medicines on the Australian Register of Therapeutic
Goods (ARTG) that introduce a new dosage form that
would not be financially viable in the absence of a TGA
fee waiver.
Europe
The pediatric program offers incentives for
drug formulations that aim to achieve dosage
forms that are more suitable than existing
formulations for children. Read more here.
Guideline on Manufacture of The Finished
Dosage Form

Canada
The recommended single and daily dosage of a drug
(a) intended to be burned and the smoke inhaled may
be increased to 10 times the oral dose, and
(b) intended for use as suppositories may be increased
to 33 1/3 per cent in excess of the oral dose.
Validation Guidelines for Pharmaceutical Dosage Forms
(GUI-0029)

US
Dosage Form Drug Manufacturers cGMPs
(10/93)
Oral Solid Dosage Forms Pre/Post Approval
Issues (1/94)
 Dalton's Services

Dalton has specialized in the development, manufacture and sterile fill/finish of

pharmaceutical and biotechnology products for over 15 years. We offer aseptic
filling and terminally sterilized products in a variety of finished dosage forms.
Dalton can support your needs for clinical development, through to small scale
commercial batches.

Formulation Development
Oral Immediate Release
Oral Controlled Release
Topical and Transdermals
Sterile Liquids
Powders
Sterile liquid dosage formulations
Injectable drugs
Lyophilized formulations

Formulation Services and Capabilities

Formulation development for new chemical entities
Optimization of existing formulations
Product/Process Optimization
Novel formulations for improved delivery of
existing dosage forms
Controlled release and sustained release
formulations
Self-emulsifying drug delivery systems
Colloidal drug delivery systems
Sub-micron and nano-emulsions
Feasibility Studies
Excipient Compatibility selection and optimization
Physico-Chemical Testing
Process Scale-Up
Technology Transfers
Batch manufacture

For more on our formulation development services, click here.

For our API process development services, click here.

 REFERENCES

1. Health Canada. (2014). Active Pharmaceutical Ingredients - Good Manufacturing

Practices - Questions and Answers. Government of Canada.
https://www.canada.ca/en/health-canada/services/drugs-health-
products/compliance-enforcement/information-health-product/drugs/active-
pharmaceutical-ingredients-questions-answers.html

2. Levy, S. (2019). Form Selection in API Development and Manufacturing, In the Context
of "Phase-Appropriateness” American Pharmaceutical Review.
https://www.americanpharmaceuticalreview.com/Featured-Articles/359472-Form-
Selection-in-API-Development-and-Manufacturing-In-the-Context-of-Phase-
Appropriateness/
3. Jacob, A. B. Nair, P. N. Patil, B. P. Panda (2019). Solid State Crystallinity, Amorphous
State, And Its Implications in The Pharmaceutical Process. International Journal of
Pharmaceutical Sciences and Research. https://ijpsr.com/bft-article/solid-state-
crystallinity-amorphous-state-and-its-implications-in-the-pharmaceutical-process/?
view=fulltext
4. Humber College. (2021). REGA 5022 Lecture 7. Blackboard@Humber REGA5022.
https://learn.humber.ca
5. Thomas, M. (2005). Importance of Powder Density in Solid Dosage Form.
Pharmaceutical Online. https://www.pharmaceuticalonline.com/doc/importance-of-
powder-density-in-solid-dosage-0001
6. Savjani, K. T., Gajjar, A. K., & Savjani, J. K. (2012). Drug Solubility: Importance and
Enhancement Techniques. Hindawi.
https://www.hindawi.com/journals/isrn/2012/195727/

7. Naveed, S., Basheer, S., Qamar, F. (2016). Stability of A Dosage Form And Forced
Degradation Studies. Journal of Bioequivalence and Bioavailability.
https://www.longdom.org/open-access/stability-of-a-dosage-form-and-forced-
degradation-studies-jbb-1000292.pdf
8. Dosage Form Design: Pharmaceutical and Formulation Considerations. Drug Dosage
Form and Drug Delivery System Design.
http://downloads.lww.com/wolterskluwer_vitalstream_com/sample-
content/9780781779340_Allen/samples/Chapter04.pdf?bcsi-ac-
cb9d8bb8a6cf43ef=254EB98B00000004wPv3ZhoesmE6fieA
tnwK9n8Wi/eAgAABAAAANMt4QAgHAAAJAAAAMe0BAA=
9. Wening, K., Breitkreutz, J. (2011). Drug Dosage Form. Science Direct
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-
science/drug-dosage-form
10. (n.d.) Dosage Form Design. BS Publications.
http://bspublications.net/downloads/05805bfacb3933_Ch-1_Pharmaceutical Dosage
form_Kamlesh.pdf

11. Muungo, L.T. (2016). Dosage Form Design: Pharmaceutical and Formulation
Consideration. SlideShare. https://www.slideshare.net/makoye1954/dosage-form-
design-62540978
 12. Robin, K. (2017). A Breakdown of Dosage Forms. Natural Products Insider.
https://www.naturalproductsinsider.com/contract-manufacturing/breakdown-dosage-
forms

13. Verica Ivanovska, PharmD, MPH Carin M.A. Rademaker, PharmD, PhD, Liset van Dijk,
PhD, and Aukje K. Mantel-Teeuwisse, PharmD, PhD. (2014). Pediatric Drug Formulations: A
Review of Challenges and Progress. ResearchGate.
https://www.researchgate.net/figure/Potential-Clinical-Advantages-and-
Disadvantages-of-Different-Formulations-and-Routes-of_tbl1_263935725

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Peter Pekos