preformulation of tablet dosage form

8/13/2019 Preformulation of Tablet Dosage Form

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Teknologi Farmasi II - PadatNajma Annuria Fithri, S.Farm., MSc., Apt.

Universitas SriwijayaGenap 2013/204


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Solid dosage form (tablet) -

PreformulationPertemuan ke - 2


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Concept of quality

What is quality?

Consumer returns not goods being returned


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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


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What is quality for dosage form?

1. Efficacy

2. Safety

3. Acceptability

4. Stability


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What is quality for dosage form based

on?1. Formula

2. Method

3. Process

4. Equipments/Tools

5. Packaging


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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


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History of Preformulation


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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)


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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


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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)


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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)


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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


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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


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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)


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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


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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


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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


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Solubility and dissolution


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Purity

Correlates with efficacy and safety of a drug.

Products used in a drug MUSTbe pharmaceuticalgrade

Quality specification are specified in pharmacopeia


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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


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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


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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


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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


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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


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Stability

5 categories of stability that needs to be takeninto account:

1. Chemical

2. Physics

3. Microbiologic

4. Therapeutic

5. Toxicologic


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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)


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preformulation of tablet dosage form

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