preformulation of tablet dosage form
TRANSCRIPT
-
8/13/2019 Preformulation of Tablet Dosage Form
1/33
Teknologi Farmasi II - PadatNajma Annuria Fithri, S.Farm., MSc., Apt.
Universitas SriwijayaGenap 2013/204
-
8/13/2019 Preformulation of Tablet Dosage Form
2/33
Solid dosage form (tablet) -
PreformulationPertemuan ke - 2
-
8/13/2019 Preformulation of Tablet Dosage Form
3/33
Concept of quality
What is quality?
Consumer returns not goods being returned
-
8/13/2019 Preformulation of Tablet Dosage Form
4/33
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
-
8/13/2019 Preformulation of Tablet Dosage Form
5/33
What is quality for dosage form?
1. Efficacy
2. Safety
3. Acceptability
4. Stability
-
8/13/2019 Preformulation of Tablet Dosage Form
6/33
What is quality for dosage form based
on?1. Formula
2. Method
3. Process
4. Equipments/Tools
5. Packaging
-
8/13/2019 Preformulation of Tablet Dosage Form
7/33
Preformulation
It is essential that certain f u n d ame n t a l physicaland chemical properties of the drug molecule andother de r i v e d properties of the drug powder aredetermined. This information dictates many of thesubsequent events and approaches in formulationdevelopment. This first learning phase is known as
p r e f o r m u l a t i o n
-
8/13/2019 Preformulation of Tablet Dosage Form
8/33
History of Preformulation
-
8/13/2019 Preformulation of Tablet Dosage Form
9/33
What is preformulation?
Preformulasi adalah pengamatan (investigasi)sifat fisika, kimia bahan aktifbaik sendiri maupundalam kombinasinya dengan eksipien dengan
tujuan untuk memperoleh informasi lengkaptentang hal-hal penting dalam pengembangansuatu bentuksediaan yang stabil dan bermutu
(berkualitas)
-
8/13/2019 Preformulation of Tablet Dosage Form
10/33
Purpose of preformulation
To establish and discover necessaryphysicochemical properties of new substances
To determine its kinetic rate profile
To establish its physical characteristic
To establish its compatibility with excipients
-
8/13/2019 Preformulation of Tablet Dosage Form
11/33
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 (BiopharmaceuticalClassification System)60% of drugs are either Class 2 (low solubility) orClass 4 (low solubility and low permeability)
-
8/13/2019 Preformulation of Tablet Dosage Form
12/33
-
8/13/2019 Preformulation of Tablet Dosage Form
13/33
-
8/13/2019 Preformulation of Tablet Dosage Form
14/33
Properties Observed in Preformulation1. Organoleptic2. Partition coefficient
3. Acid/base dissociation constant and permeabilitythrough biological membrane (pKa, pKb)4. Solubility (intrinsic, apparent) and dissolution5. Purity6. Polymorphism and crystal form7. Surface characteristic (surface area, porosity, pore
volume)8. Flowability9. Compactibility/compressibility
10. Wettability11. Other (hygroscopicity, density, melting point, vapour
pressure)
-
8/13/2019 Preformulation of Tablet Dosage Form
15/33
Organoleptic Using senses
Qualitative result
Usefulmasking bitter taste (ex: chloramphenicol)
Beberapa terminologi yang digunakan untuk
mendeskripsikan serbukWarna Bau Rasa
Putih buram Tajam Asam
Krim kekuningan Sulfurous Pahit
Coklat Aroma buah LembutMengkilap Aromatik Kuat
Tidak berbau Manis
Tidak berasa
-
8/13/2019 Preformulation of Tablet Dosage Form
16/33
Partition coefficientWhat is it?
The ratio of the concentrations of a solute in twoimmiscible or slightly miscible liquids
PC = C (np)/C (p)
Why?
Biological membranelipophilic
Correlates with solubility
-
8/13/2019 Preformulation of Tablet Dosage Form
17/33
pKa/pKb and membran permeabilityWhat? quantitative measure of the strength of an acidin solution
Majority of drugs are in weak acid/base formIn the presence of liquid, there will be ionized andunionized form
Henderson-HasselbachpH = pKa + log (i)/log(ui)
Drugs should be targeted for absorption at itscompatible/correct biological location (+/- 1-2 of itspKa/pKb)
-
8/13/2019 Preformulation of Tablet Dosage Form
18/33
pKa/pKb and membran permeability
Unionizedless polarpass through biological
membrane easier
%ionization = I / I+UI x 100%
Drugs absorption transport system: passivediffusion, active transport, facilitated transport
Partition pH hypothesis = most drugs areabsorbed from GI through passive diffusion,
which amount relative towards the fraction of
unionized drugs
-
8/13/2019 Preformulation of Tablet Dosage Form
19/33
Solubility and dissolutionSolubility = static
Dissolution = rate process
Solubility is the analytical composition of a
saturated solution expressed as a proportion of adesignated solute in a designated solvent.
Dissolution is the processby which a solute formsa solution in a solvent. Dissolution is a kineticprocess and it is quantified by its rate
-
8/13/2019 Preformulation of Tablet Dosage Form
20/33
Solubility and dissolution
Rate of dissolution can affect onset, duration,response intensity as well as bioavailability ofdrugs.
Noyes whitney equation (rate of dissolution)
dM/dt = DS(Cs-C)/h
-
8/13/2019 Preformulation of Tablet Dosage Form
21/33
Solubility and dissolution
-
8/13/2019 Preformulation of Tablet Dosage Form
22/33
Purity
Correlates with efficacy and safety of a drug.
Products used in a drug MUSTbe pharmaceuticalgrade
Quality specification are specified in pharmacopeia
-
8/13/2019 Preformulation of Tablet Dosage Form
23/33
PolymorphismRaw material drugs are usually in crystalline and
amorph form
Useful information to gain knowledge about efficacyand stability
Ex: novobiosin and chloramphenicol palmitate hasbetter efficacy in amorf form
Crystalline form usually has lower internal energy,thermodinamically more stable than amorph, so oftenless soluble than amorph form
-
8/13/2019 Preformulation of Tablet Dosage Form
24/33
Surface characteristicHas effect on mixing and formulation of tablets (especially onfluidity)
Drugs with spheric shape flow better (v,s = 6). The bigger v,sthe more amorf the particle. With the same diameter but biggerv,s the fluidity of particle is less.
Drugs smaller particle size has better dissolution but lessen thefluidity 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
-
8/13/2019 Preformulation of Tablet Dosage Form
25/33
-
8/13/2019 Preformulation of Tablet Dosage Form
26/33
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
-
8/13/2019 Preformulation of Tablet Dosage Form
27/33
Compressibility and compactibility
Compactibility: is the ability of the powdered
material to be compressed into a tablet of specifictensile strength Compressibility: its ability to decrease in volume
under pressure
Compact: static Compress: dinamic
Correlates with particle deformation in tabletcompression
-
8/13/2019 Preformulation of Tablet Dosage Form
28/33
-
8/13/2019 Preformulation of Tablet Dosage Form
29/33
-
8/13/2019 Preformulation of Tablet Dosage Form
30/33
WettabilityHas effect on granulation, water penetration
(disintegration) and adhesion of material (in coating)
Wettability = sudut kontak yang terbentuk antaracairan dan padatan
Hydrophobiccontact angle = 90 degrees
Can be improved with surfactant andhydrophilization
-
8/13/2019 Preformulation of Tablet Dosage Form
31/33
Stability
5 categories of stability that needs to be takeninto account:
1. Chemical
2. Physics
3. Microbiologic
4. Therapeutic
5. Toxicologic
-
8/13/2019 Preformulation of Tablet Dosage Form
32/33
Others
Density compactibility, compressibility
Vapour pressurelost of active ingredients,interaction with excipents, adsorption/sorption
into packaging Melting pointmanufacture consideration
(drying/heating), also for purity
Hygroscopicitymanufacture consideration(humidity), interaction with excipients, shelf life(stability)
-
8/13/2019 Preformulation of Tablet Dosage Form
33/33