padat pertemuan 4 - manufacturing

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

Universitas SriwijayaGenap 2013/2014

Pertemuan ke - 4Manufacture Process – Part 1

General Flow Process

Active Compound

Excipients

Mixing

Granulation

Drying

Compression

Packaging

Powder

Milling• Grinding a drug in a mortar to reduce its particle

size is termed trituration or comminution

Advantages of trituration:1. Increase surface area of contact increase

solubility increase bioavailability2. Increase content uniformity3. Optimized particle size and its distribution can

increase fluidity4. Increased dispersion of colours5. In wet granulation, can increase efficiency of

drying

Milling• Disadvantages of trituration:1. Smaller particles tend to create aggregates2. Particle polymorphism may change cause of

instability, may even reduce potency3. Increase of air moisture adsorption instability

MixingPurpose of mixing: to achieve a homogenous mixture

Types of mixture:1. Positive mixture2. Negative mixture3. Neutral mixture powder mix

Mixing mechanism:1. Convective mixing2. Shear mixing3. Diffusive mixing

MixingFactors influencing mixing of solids (powder):• Particle characteristics (shape, size, distribution)• Density• Adherence forces (fluidity)• Electrostatic forces• Humidity• Mixing time• Tools of mixing (mixers type)

Optimum Mixing

• Rotation speed needs to be optimizedToo slow Does not produce tumbling or cascading motion. Does not generate rapid shear rate.Too fast creates centrifugal force, cause powder to stick to the walls of mixer

Equipments in mixing

• Batch mixing equipmentTumbling mixer (twin-shell, cube, cylindrical)Ribbon mixer

• Continuous mixing equipment

MixingSegregation = an undesirable separation of the different components of the blend.

• Segregation may occur by sifting or percolation, air entrapment (fluidization), and particle entrapment (dusting)

Steps to avoid segregation while mixing:• Minimum number of transfer steps (drop weight)• Control of dust generation• Control of fluidization of powder• Slow fill/transfer rate• Appropriate venting• Use of deflector/vane• Proper use of hopper

Measures of mixing degree

µ = number of particles of the fractionτ = standard deviationn = number of total particlesp = number of fraction of particles

Measures of mixing degree•

Measures of mixing degree

%CV = SD x 100%

CV = coefficient variationSD = standard deviationn = number of total particlesp = number of fraction of particles

Measures of mixing degree•

Calculation in Tablet Dosage Form

• Internal phase (Active Ingredient + Filler + Binder + Disintegrant)

• External phase (Lubricant + Glidant + Antiadherent)

Contoh 1

Formula: Untuk 1000 tablet

Asetosal 500 gGelatin 10% qsLaktosa qsAmilum 10% bobot tabletTalkum 2%Asam stearat 3%

Bobot akhir yang diinginkan = 700 mg

Talk = 2/100 x 700 = 14 gAsam stearat = 3/100 x 700 = 21 gTotal FL = 35 g

Amilum = 10% x 700 = 70 gLaktosa = 700 – (500 + 35) = 165 g

Gelatin 10% yang dibutuhkan untuk 3ooo g = 290 mLJadi = 290/3000 x 165 = 15,95 mL

Gelatin yang dibutuhkan = 10 g/100 mL x 15,95 mL = 1,595 g

Example Formula (wet granulation)A. Contoh: ZA paracetamol 500 mg

Direncanakan bobot tablet 700 mg dibuat 1000 tablet 1 x produksi. Dari hasil IPC diketahui granul FD berbobot 600 g dengan kadar air 2%. Formula:

Paracetamol 500 gAmilum 10% dari bobot tabletMusilago amili 10% (1/3 FD)Laktosa qsMg stearat 1%Talk 2%Amilum kering 5%

Tentukan jumlah serta bobot tablet yang diperoleh. Serta tentukan jumlah masing masing excipient yang dibutuhkan.

Fase Luar teoritis (1+2+5 = 8%)Mg stearat = 1/100 x 700 = 7 gTalk = 2/100 x 700 = 14 gAmilum kering = 5/100 x 700 = 35 gTotal FL =56 g

Fase dalam (92%) Paracetamol = 500 g Amilum = 10% x 700 g = 70 gMusilago amili 10% (1/3 FD) = ?Laktosa = ?

FD = (Total Bobot yg diinginkan – FL)= 700 – 56 = 644 g

Musilago amilum 10% = 1/3 x 644 x 10% = 21,47 g Laktosa = 644 – (500 +70 + 21,5) = 52,5 g

Dari hasil IPC diketahui granul FD berbobot 600 g dengan kadar air 2%

Fase luar yang ditambahkan:- Mg stearat = 1/92 x 600 = 6,52 g- Talk = 2/92 x 600 = 13,04 g- Amilum kering = 5/92 x 600 = 32,60 gTotal FL = 52,16 g

Moisture content dari 2% 0%Bobot granul = 98/100 x 600 = 588 g

Jumlah tablet yang diperoleh dari hasil granulsebelum kempa = 588/644 x 1000 = 913,04 tablet

Bobot tablet akhir = (600 g + 52,16 g)/913,04= 714,27 mg

Contoh 3 (Dry granulation)Formula: Untuk 1000 tabletIbuprofen 400 gAmilum 10% bobot tabletLaktosa qsMg Stearat 1%Talk 2%

Jumlah FL yang ditambahkan secara internal = 50%Bobot akhir tablet yg diinginkan = 600 mg

Dari hasi IPC diketahui slug yang terbentuk sebanyak500 g

Fase luar (1+2 = 3%)Mg stearat = 1/100 x 600 = 6 gTalk = 2/100 x 600 = 12 gTotal FL = 18 gJumlah yang dicampur ke FD:- Mg stearat = 50/100 x 6 = 3 g- Talk = 50/100 x 12 = 6 g

Fase dalam:Ibuprofen = 400 gAmilum = 10% x 600 g = 60 gLaktosa = 600 – (400+60+18) = 122 g

Total bobot fase dalam sebelum slugging = 9 + 400 + 60 + 122 = 591 g

• Diketahui slug yang diperoleh = 500 g

Sisa Fase luar yang ditambahkan- Mg stearat = 500/591 x 3 g = 2,54 g- Talk = 500/591 x 6 = 5,08 g

Bobot total = slug + sisa FL = 500 + 5,08 + 2,54 = 507,62 g

Jumlah tablet yang diperoleh = 500/591 x 1000 = 846,02 tabletBobot @ tablet = 507,62 g / 846,02 = 0,600 g = 600 mg