Design of Drug Formulations

Introduction

VO CHE.873UB
WS 2021/22

Mag. pharm. Dr. Nikola Kitic

Scheduled dates

▪ Introduction 04.11.2021 09 – 12
▪ Liquid drug forms 09.11.2021 09 – 12
▪ Sterile drug forms I 11.11.2021 09 – 12
▪ Sterile drug forms II 16.11.2021 09 – 12
▪ Semisolid drug forms 18.11.2021 09 – 12
▪ Suppositories 23.11.2021 09 – 12
▪ Solid drug forms I 25.11.2021 09 – 12
▪ Solid drug forms II 30.11.2021 09 – 12
▪ Modern drug forms 02.12.2021 09 – 12
▪ Herbal drug forms 07.12.2021 09 – 12
▪ Exam TBA
Moodle

▪ https://moodle.uni-graz.at
Drug formulation

▪ Drug formulation = Pharmaceutical Technology = galenical development

▪ Preparation of pharmaceutical products out of medical substances

▪ Active pharmaceutical ingredient (API):

biological active compound of the dosage form

▪ Excipients:
usually “inactive” substances
carrier- or shaping substances
support or regulation of the effect
Drug formulation

▪ Pharmaceutical product = drug form

consists of one or more active pharmaceutical ingredients and excipients
produced by physical process steps

▪ Dosage form
form in which a medicine is administered
conversion of drug form into dosage form before application

Pharm. product =/≠ Dosage form Comment

tablets = tablets unmodified swallowed
cream = cream unmodified applied
concentrated juice ≠ suspension administration after addition of water
effervescent powder ≠ oral solution dissolving under release of CO2
Drug formulation

▪ Types of pharmaceutical products

▪ Extemporaneous mixtures
manufactured individually due to a prescription or customer demands in the pharmacy
▪ Small scale productions
produced in bulk to keep in stock in the pharmacy because of frequent doctor's prescription
▪ Finished pharmaceuticals
industrial production of packed drugs
Drug formulation

▪ Targets:
▪ transfer of APIs into drug forms to assure accurate dosing
▪ stabilization of API
▪ masking of bad taste or smell
▪ control of liberation and absorption of the API
▪ drug targeting
Drug formulation - film
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Preformulation
▪ particle size and surface area
▪ solubility
▪ dissolution
▪ permeation rate (partition coefficient and pKa)
▪ crystal properties
▪ stability
▪ organoleptic properties
▪ hygroscopicity, flowability, compactibility,…
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Therapeutic considerations
▪ need for local or systemic therapy
▪ required duration of action
▪ emergency or chronic therapy
▪ age of patient
▪ weight
▪ special physiologic and metabolic factors
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Administration route
▪ parenteral
▪ topical
▪ buccal
▪ oral
▪ intranasal
▪ pulmonary
▪ vaginal
▪ rectal
Pharmacokinetics

▪ LADME – model ▪ Example: intake of tablets…

▪ liberation
▪ absorption
▪ distribution
▪ metabolism
▪ excretion
 Liberation
Liberation

▪ Drug release and dissolution in the digestive juices of gastrointestinal tract

▪ Drug release influenced by galenical development

▪ For the dissolution the API must have hydrophilic properties

▪ Dissolution rate can be affected by particle size of the API

 Absorption

Absorption

▪ Absorption of the API from site of administration in the bloodstream or the lymphatic
system through biological membranes (e.g. gastrointestinal mucosa)

▪ API must be lipophilic to accumulate in the cell membrane

▪ → Amphiphilic APIs necessary to achieve liberation and absorption

▪ Residence time crucial for absorption → depends on fluid and food intake
 Distribution
Distribution

▪ Distribution of the API between the bloodstream and tissues / organs

▪ Barriers for some APIs:

▪ blood-brain-barrier
▪ kidney barrier

▪ Binding of APIs to proteins of the plasma → long-term form

▪ Effect by interacting with receptor molecules

 Metabolism

Metabolism

▪ Biotransformation of lipophilic molecules

▪ in the liver
▪ oxidation
▪ reduction
▪ hydrolysis
▪ glucuronidation

▪ 1st – Pass – Effect

 Excretion

Excretion Excretion

▪ Elimination from the organism

▪ kidneys
▪ bile
▪ intestine
▪ lung
▪ skin
Pharmacokinetic parameters

▪ Bioavailability = rate and extent to which an API is released from a drug form and
appears in the blood or at the site of action
▪ AUC → extent of bioavailability
▪ Cmax → maximum concentration of the drug in the blood
▪ Tmax → rate of drug release
▪ MEC → minimum effective concentration
▪ MTC → minimum toxic concentration
Pharmacokinetic parameters

▪ Clearance = virtual blood-/plasma volume, which is freed from API per unit time
▪ total body clearance (hepatic and renal):

CL = D*F/AUC

D … dosage
F … bioavailability

▪ Half-life period (t ½) = time in which the plasma concentration drops to the half
▪ assess the duration of action
▪ establishing a dosing pattern
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form individual units
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Excipients

▪ Optimization of drug therapy and compliance (therapy adherence)

Main function Group of excipients Examples

enabling an applicable form filling materials corn starch to form a tablet for highly
effective glycosides (dose <1 mg)

prolonging the release retarding polymers polymer film on the capsule shell
enteric resistance pH-sensitive polymers enteric resistant film on granules (API e.g.
acid-labile)

extended shelf life preservatives benzalkonium chloride in ear drops

improving processing flow regulating agent, colloidal SiO2 in filling material of capsules,
parting agent silicon oil in suppository moulds with cocoa
butter

cosmetic function dermal base, ointment hydrous wool wax alcohol ointment for
base various skin diseases

improving compliance taste corrigents, coatings sweeteners in antibiotic suspensions,

methyl cellulose films on malodorous or bad-
tasting tablets
Excipients

▪ Requirements:
▪ therapeutically indifferent
▪ physiologically harmless and non-toxic
▪ no carriers of pathogens
▪ chemically and physically stable and compatible with API
▪ no adverse changes to the function of the drug form

▪ Classification:
▪ ionic excipients
▪ non-ionic excipients
▪ amphoteric excipients
Water for pharmaceutical use

▪ Production by:
▪ ion exchange:
ion exchangers = polymer resins
separated-bed and mixed-bed process
▪ distillation:
thermal separation process
separation of organic as well as inorganic ingredients from water
▪ reverse osmosis:
osmosis = diffusion of water through a semipermeable membrane to ion-containing side
osmotic pressure
applying a pressure on the ion-containing side reverts osmotic process → reverse osmosis
Requirements for water acc. to Ph. Eur.

▪ Purified water:
▪ for the preparation of oral drugs
▪ neither sterile nor free of pyrogens
▪ purification of drinking water by distillation, ion exchange, reverse osmosis, ...

▪ Highly purified water:

▪ to produce particularly pure oral drugs
▪ not for parenteral use and eye medicines
▪ purification of drinking water e.g. by double reverse osmosis

▪ Water for injection:

▪ production of sterile dosage forms (parenteral and ophthalmic)
▪ sterile and free of pyrogens
▪ purification of drinking water or purified water by heat treatment
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Manufacturing processes
▪ consist of several basic operations
▪ basic operations = mechanical or thermal procedures that are constantly used in the
manufacture of pharmaceutical products
e.g. milling, weighing, sieving, filtering, mixing, drying, ...

▪ Manufacturing process for wet granulation:

▪ weigh
▪ mix
▪ humidify
▪ shred
▪ dry
▪ sieve
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Packaging
▪ primary packaging materials: inner containers, direct contact with drug form (glass, plastics,
metals)
glass  good drainability, transparency or protection from light
 fragile, release of alkalis
plastics  good formability in heat (blister packaging for tablets and capsules)
 absorption of APIs and excipients
metal  high tightness and mechanical strength
 coating needed

▪ secondary packaging material:

outer wrappings, e.g. cardboard boxes
▪ packaging adjuvants:
e.g. measuring spoon
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Quality tests acc. to Eur. Ph.

▪ Uniformity of mass (2.9.5 or 2.9.27):
▪ determination of the average mass from 20
samples of the dosage form, evaluation of
deviations from the average mass according to
pharmacopoeia
▪ from the prepared batch only 2 dosage forms
may deviate more than the allowed value, no
one more than twice
▪ Uniformity of content (2.9.6):
▪ determination of the average API content from
10 samples of the dosage form, evaluation of
deviations from the average API content
according to pharmacopoeia
▪ from the prepared batch only 1 dosage
form is allowed to be outside the limits of 85-
115%, no one outside 75-125%

Single dose drug content

≤ 2 mg or ≤2%

No Yes

Uniformity of Uniformity of
mass content
Drug formulation

▪ Quality tests acc. to Eur. Ph.

▪ Drug release (2.9.3)

▪ paddle stirrer
closed system
▪ rotating basket

tablet

outlet
filter head

sample
▪ flow cell open system chamber
glass beads cell body
valve

inlet
Drug formulation

▪ Quality tests acc. to Eur. Ph.

▪ Drug release (2.9.3)
▪ Release media

Medium pH Simulation
water 7.0 aqueous release in any specific area of the body
fluids
0.1 N HCl 1.0 release in the stomach
phosphate buffer ca. 6.8 release in the small intestine
phosphate buffer ca. 7.3 release in the colon
Drug formulation

▪ Formulation development
▪ search for new APIs
▪ pharmacological tests in animal studies (phase 0)
▪ preformulation of the API
▪ therapeutic considerations
▪ administration route → pharmacokinetics
▪ drug/dosage form
▪ excipients
▪ manufacturing process clinical trials in humans (phase 1 - 3)

▪ packaging + label
▪ quality tests
▪ drug approval and further monitoring of adverse reactions (phase 4)
Drug formulation

▪ Drug approval
Austrian Federal Office for Safety in Healthcare (BASG) → approvals Austria
European Medicinal Evaluation Agency (EMEA) → approvals Europe
US Food and Drug Administration (FDA) → approvals USA
▪ documents about quality, safety and efficacy are required

▪ Generics
= cheaper successor preparations
Legal framework

▪ Definitions and rules for the production and testing of drugs

▪ “Arzneimittelgesetz” (AMG) = law for pharmaceuticals

▪ deals with definitions, requirements and production of pharmaceuticals, clinical trials, quality
controls,…

▪ “Apothekenbetriebsordnung” = work rules for pharmacies

▪ regulates conditions for the proper operation of a pharmacy
GMP - Good Manufacturing Practice

▪ = Guidelines for quality assurance of the production processes and production

environment during the production of pharmaceuticals

▪ Basics of GMP – rules:

▪ accuracy in all operations including packaging and storage
▪ prevent mix-ups
▪ avoid contamination
▪ production hygiene
▪ documentation of all manufacturing operations
▪ quality control system
Legal framework

▪ Pharmacopoeia (ÖAB, EAB & HAB)

▪ collection of pharmaceutical rules on quality, testing, storage, dispensation and designation of
pharmaceuticals
▪ general section (instructions for general methods of analysis)
▪ monographs (definitions of monographed subject, descriptions of identity tests, purity tests
and determinations of content, storage instructions)

▪ “Deutscher Arzneimittel Codex” (DAC) & “Neues Rezepturformularium” (NRF)

▪ rules for working practice in pharmacies and collection of formulations