Teknologi Farmasi II - Padat

Najma Annuria Fithri, S.Farm., MSc., Apt.

Universitas Sriwijaya
Genap 2013/204
Solid dosage form (tablet) -
Preformulation
Pertemuan ke - 2
Concept of quality
What is quality?
Consumer returns not goods being returned
Concept of Quality
Quality does not just happen
Quality has to be designed and built into a product
during the entire manufacturing process
This process has to be validated
What is quality for dosage form?
1. Efficacy
2. Safety
3. Acceptability
4. Stability
What is quality for dosage form based
on?
1. Formula
2. Method
3. Process
4. Equipments/Tools
5. Packaging
Preformulation
It is essential that certain fundamental physical
and chemical properties of the drug molecule and
other deri ved properties of the drug powder are
determined. This information dictates many of the
subsequent events and approaches in formulation
development. This first learning phase is known as
preformulati on
History of Preformulation
What is preformulation?
Preformulasi adalah pengamatan (investigasi)
sifat fisika, kimia bahan aktif baik sendiri maupun
dalamkombinasinya dengan eksipien dengan
tujuan untuk memperoleh informasi lengkap
tentang hal-hal penting dalampengembangan
suatu bentuk sediaan yang stabil dan bermutu
(berkualitas)
Purpose of preformulation
To establish and discover necessary
physicochemical properties of new substances
To determine its kinetic rate profile
To establish its physical characteristic
To establish its compatibility with excipients
New compound preformulation
Two fundamental properties are mandatory for a
new compound:
1. Intrinsic solubility (C0)
2. Dissociation constant (pKa) lipophilicity
Why?
Correlates with BCS (Biopharmaceutical
Classification System)
60% of drugs are either Class 2 (low solubility) or
Class 4 (low solubility and low permeability)
Properties Observed in Preformulation
1. Organoleptic
2. Partition coefficient
3. Acid/base dissociation constant and permeability
through biological membrane (pKa, pKb)
4. Solubility (intrinsic, apparent) and dissolution
5. Purity
6. Polymorphism and crystal form
7. Surface characteristic (surface area, porosity, pore
volume)
8. Flowability
9. Compactibility/compressibility
10. Wettability
11. Other (hygroscopicity, density, melting point, vapour
pressure)
Organoleptic
Using senses
Qualitative result
Useful masking bitter taste (ex: chloramphenicol)
Beberapa terminologi yang digunakan untuk
mendeskripsikan serbuk
Warna Bau Rasa
Putih buram Tajam Asam
Krimkekuningan Sulfurous Pahit
Coklat Aroma buah Lembut
Mengkilap Aromatik Kuat
Tidak berbau Manis
Tidak berasa
Partition coefficient
What is it?
The ratio of the concentrations of a solute in two
immiscible or slightly miscible liquids
PC = C (np)/C (p)
Why?
Biological membrane lipophilic
Correlates with solubility
pKa/pKb and membran permeability
What? quantitative measure of the strength of an acid
in solution
Majority of drugs are in weak acid/base form
In the presence of liquid, there will be ionized and
unionized form
Henderson-Hasselbach
pH = pKa + log (i)/log(ui)
Drugs should be targeted for absorption at its
compatible/correct biological location (+/- 1-2 of its
pKa/pKb)
pKa/pKb and membran permeability
Unionized less polar pass through biological
membrane easier
%ionization = I / I+UI x 100%
Drugs absorption transport system: passive
diffusion, active transport, facilitated transport
Partition pH hypothesis = most drugs are
absorbed from GI through passive diffusion,
which amount relative towards the fraction of
unionized drugs
Solubility and dissolution
Solubility = static
Dissolution = rate process
Solubility is the analytical composition of a
saturated solution expressed as a proportion of a
designated solute in a designated solvent.
Dissolution is the process by which a solute forms
a solution in a solvent. Dissolution is a kinetic
process and it is quantified by its rate
Solubility and dissolution
Rate of dissolution can affect onset, duration,
response intensity as well as bioavailability of
drugs.
Noyes whitney equation (rate of dissolution)
dM/dt = DS(Cs-C)/h
Solubility and dissolution
Purity
Correlates with efficacy and safety of a drug.
Products used in a drug MUST be pharmaceutical
grade
Quality specification are specified in pharmacopeia
Polymorphism
Raw material drugs are usually in crystalline and
amorph form
Useful information to gain knowledge about efficacy
and stability
Ex: novobiosin and chloramphenicol palmitate has
better efficacy in amorf form
Crystalline form usually has lower internal energy,
thermodinamically more stable than amorph, so often
less soluble than amorph form
Surface characteristic
Has effect on mixing and formulation of tablets (especially on
fluidity)
Drugs with spheric shape flow better (v,s = 6). The bigger v,s
the more amorf the particle. With the same diameter but bigger
v,s the fluidity of particle is less.
Drugs smaller particle size has better dissolution but lessen the
fluidity and stability
Classification:
- COARSE POWDER : 1000 m
- CONVENTIONAL POWDERS : 50 1000 m
- FINE PARTICLES : 1 50 m
- SUB MICRON PARTICLES : 0,1 1 m
- MICRONIZED : < 0,1 m
Flowability/fluidity
Has effect on tablet formulation, mixing and
weight uniformity.
Factors that influence fluidity of powder:
- Particle size
- Shape of particles
- Density of particle
- Porosity of pwder
- Electrostatic forces
- Humidity
Compressibility and compactibility
Compactibility: is the ability of the powdered
material to be compressed into a tablet of specific
tensile strength
Compressibility: its ability to decrease in volume
under pressure
Compact: static
Compress: dinamic
Correlates with particle deformation in tablet
compression
Wettability
Has effect on granulation, water penetration
(disintegration) and adhesion of material (in coating)
Wettability = sudut kontak yang terbentuk antara
cairan dan padatan
Hydrophobic contact angle = 90 degrees
Can be improved with surfactant and
hydrophilization
Stability
5 categories of stability that needs to be taken
into account:
1. Chemical
2. Physics
3. Microbiologic
4. Therapeutic
5. Toxicologic
Others
Density compactibility, compressibility
Vapour pressure lost of active ingredients,
interaction with excipents, adsorption/sorption
into packaging
Melting point manufacture consideration
(drying/heating), also for purity
Hygroscopicity manufacture consideration
(humidity), interaction with excipients, shelf life
(stability)