Metode pembuatan Jenis pemeriksaanBahan/tahap

Kempa langsung Massa cetak Sifat aliranHomogenitas campuran

Granulasi kering Massa granul Sifat aliranBj ruah/Bj nyataBj mampat

Granulasi basah Massa granul Sifat aliranBj ruah/Bj nyataBj mampatKandungan lembab

EVALUASI MASSA CETAK (IN PROCESS CONTROL)

POWDER FLOW PROPERTIES

• During many pharmaceutical production processes it is necessary to transfer large quantities of powder from one location to another in a controlled manner– Powder blending– Powder filling into containers (e.g. dusting powders)– Powder flow into capsules– Powder filling into the dies of a tablet press

• One method of assessing flow properties is the Angle of Repose. – Powder is allowed to flow freely

through a funnel onto the center of an upturned petri dish of known radius

– When the powder reaches the side of the petri dish the height of the cylindrical cone is determined.

– From the petri dish radius (r, cm) and cone height (h, cm) the angle of repose (between the petri dish and base of the powder cone) can be calculated.

– Remember: Tan θ = Opposite / Adjacent, therefore Tan θ = h / r.

Angle of Repose

• Flow rate can also be determined by measuring how fast a powder flows through an aperture.

– Free flowing powders exhibit a high flow rate and a smaller angle of repose.

– Angle of repose and flow rate depend on particle size, shape and surface roughness.

– Flow properties are frequently enhanced by the use of glidents.

Flow rate

REAL, TAPPED and BULK DENSITY

• The true density (ρt) of a powder sample is the weight per unit volume of the material with no air spaces between particles. – Therefore, if a material has a true density of 1 g

cm-3, 100 g of material will occupy 100 mL assuming individual particles fit together exactly.

– In practice most powders do not fit together very well.

• Therefore, if one fills a graduated cylinder to 100 mL with a powder, the weight of powder required may only be 70 g.

• This apparent density is known as the bulk or expanded density (ρb, 0.7 g cm-3).

• If the100 mL cylinder is then tapped, the particles slide past each other and become consolidated.

• The 70 g of particles which once occupied 100 mL may now only occupy 80 mL.

• They have an apparent packed or tapped density (ρp) of 0.875 g cm-3.

Carr's index

• Carr's index is a measure of interparticulate forces. • If the interparticulate forces are high, powders will have a

low bulk density because bridging will occur between particles.

• This results in a large Carr's index and a large change in volume caused by tapping.

• If the interparticulate forces are low, particles will have little affinity for one another, and will compact spontaneously.

• Under these circumstances, Carr's index is small and little change in apparent density is induced by tapping.

Kandungan lembabAlat uji kandungan lembab

Prosedur

1. Timbang granul sebanyak 5 g di atas nampan logam (aluminium)

2. Nyalakan alat, cek suhu pada 70C

3. Penetapan kandungan lembab dapat di atur skalanya pada alat (% hilang atau g hilang)

4. Penetapan dihentikan setelah dicapai angka konstant

Adalah jumlah massa (air) yang hilang selamaproses pemanasan (70C)

Tujuan

1. Mengontrol kandungan lembab granul sehingga dapat mengantisipasi masalah yang terjadi selama proses pengempaan tablet, terutama kandungan lembab menjadi faktor penyebabnya

2. Mengontrol K.L granul berkaitan dgn pertumbuhan mikroba, jika granul tidak langsung dikempa menjadi tablet

Courtesy : Heni Rachmawati, PhD (ITB)

Tablet evaluation

• Quantitative evaluations for the tablet’s chemical, physical, and bioavailability properties should be made, which include:

– General appearance– Size and shape– Identification markings– Organoleptic properties– Hardness and friability– Content uniformity– Weight variation– Disintegration and dissolution

Requirements to be set for tablets

The parameters: Crushing strength friability Uniformity of mass Uniformity of content content Disintegration time Dissolution rate Stability

Mechanical strength

Dose precision

Pharmaceutical availability

SpecificationsTypical specifications: (Immediate release):

Crushing strength : > 60 N Friability (Roche friabilator) : < 1 % Mass : individual + 5%

: mean + 2% Content of the drug : 95 -105 % Uniformity of content : individual 85-115 %

: RSD <6 % (??) Desintegration : < 15 min. Release : Q80< 45 min (30

min) Shelf life : 2 years zone 1 - 4 Related compounds :………...

General appearance

• An elegant appearance (shape, size, color, odor, taste, surface texture, imprints) of the tablet is essential for patient acceptance.

Size and shape

• The size and shape can be evaluated and controlled by measuring the dimensions of the tablet.

• The only dimension that varies with the process is the thickness. The other dimensions are controlled by the shape and size of the punch and die sets.

• Tablet thickness should be monitored and controlled during production.– It can be measured using a micrometer.

• Tablet thickness is affected by:– Compression force– Die fill– Particle size distribution

Size and shape

• Variability in tablet thickness should not exceed ±5% of a standard value.

• Variability in thickness within a particular lot can lead to:– Problems with consumer acceptance– Packaging problems– Weight variation– Content uniformity problems

Identification markings

• In addition to color, size, and shape products can be identified from their tablets using a unique marking.

• These markings can be embossed engraved or printed on the tablet surface.

Identification markings

• Websites can be used to search for product names from the tablet imprints:– Drugs.com

• http://www.drugs.com– Then click on pill identification

» Type the code in the imprint field and click search

Organoleptic properties

• Organoleptic can be defined as: relating to perception by a sensory organ.

• It includes the appearance (shiny or dull), color (uniformity), the taste (adding flavors), and the odor (e.g. aspirin) of the product.

• Visual examination of these properties is possible but with large degree of subjectivity.

• Electronic equipment for measuring color uniformity and gloss on a tablet surface can be applied.

Hardness and friability

• Tablets should have adequate strength to withstand mechanical shocks of manufacturing, packaging, shipping, and dispensing.

• Friability is defined as ease of s tablet to be broken or ease to be reduced to powder.

• Tablet strength (hardness) could be increased by increasing the compressive force employed.

• If the tablet is too hard this could negatively affect the disintegration rate.

Kekerasan Tablet

• Kekerasan tablet merupakan parameter ketahanan tablet dalam melawan tekanan mekanik seperti goncangan dan terjadinya keretakan tablet selama pengemasan, transportasi dan pemakaian.

• Alat : Hardness Tester• Cara :

– Tablet diletakkan pada posisi yang ada pada alat dan alat dihidupkan lalu baca angka yang ditunjukkan pada alat.

– Dilakukan terhadap 20 tablet yang diambil secara acak.

• Kekerasan diukur berdasarkan luas permukaan tablet dengan menggunakan beban yang dinyatakan dalam kg.

• Satuan kekerasan adalah kg/cm2. • Ditentukan kekerasan rata-rata dan standar

deviasinya.• Syarat : tablet besar : 7-10 kg/cm2 ; tablet

kecil : 4 kg/cm2, tapi harus konsisten pada salah satu angka misalnya 6.

Hardness tester

Bellstone tablet hardness tester

Friability tester

Programmable Tablet Friability Test Apparatus, Model EF-2

Friability drum

Friability test: pre-weighed tablet sample is placed in drum andoperated for 100 revolutions at 25 RPM, the tablet sample iscollected and re-weighed.

Compressed tablet are considered acceptableIf weight loss is below 1%. Effervescent andChewable tablets can show more weight loss.

Friability

• Weigh 10 tablets collectively (Wo) • Place the tablets in the friabilator. • Set timer for 4 minutes (100

revolutions) • After 4 minutes running, reweigh the

intact tablets (WF) • Report % Friability, calculated as

follows:

(Usually, < 0.8% is considered satisfactory.)

Content uniformity

• The amount of drug in each tablet need to be monitored from tablet to tablet and from batch to batch.

Pemeriksaan kadar tablet

• Diambil 20 tablet secara acak, kemudian digerus dan ditimbang seberat 1 tablet. Kadar memenuhi persyaratan bila kadar yang ditetapkan memberikan hasil dalam batas 95 % sampai 105 %.

Content uniformity

Content uniformity

• Problems in content uniformity might arise from:– Non-uniform distribution of the drug

throughout the powder mixture or granulation.

– Segregation of the powder mixture or granules during processing.

– Weight variation.

Weight variation

• The weight of the tablets being produced should be monitored and controlled to ensure that the proper amount of the drug is contained in the tablets.

• The weight variation test is satisfactory to determine the content uniformity if the active ingredient contributes to 95% or more of the tablet weight.

Keragaman Bobot

• Alat : Timbangan • Cara :

– Ditimbang 20 tablet, hitung bobot rata-rata tiap tablet, jika ditimbang satu-persatu, tidak boleh lebih dari 2 tablet yang masing-masing bobotnya menyimpang dari bobot rata-ratanya lebih besar dari harga yang ditetapkan pada kolom A dan 1 tabletpun yang bobotnya menyimpang dari bobot rata-ratanya lebih dari harga yang ditetapkan pada kolom B

Bobot rata- rata Penyimpangan bobot rata-rata dalam %

A B

25 mg atau kurang 15 30

26 mg sampai dengan 150 mg 10 30

151 mg sampai dengan 300 mg 7,5 15

Lebih dari 300 mg 5 10

Weight variation

• According to USPXX:– 20 tablets are individually

weighed and the average weight is determined.

• No more than two tablets should be outside the percentage limits.

• No tablet differs by 2 times the percentage limits.

Average weight of

tablets (mg)

Percentage limits

≤130 10

130-324 7.5

>324 5

Disintegration

• Disintegration: is the breakdown of the tablet into smaller particles or granules.

• Disintegration time: is the time required for the tablet to completely breakdown and pass through the mesh in the disintegration basket.

Disintegration basket Disintegration tester

Disintegration Time

• Place one tablet into each of the six tubes.

• Set apparatus in motion. • Estimate within + 1 minute the time

required on the average for the six tablets to disintegrate (In FI IV, not allowed after 15 minutes to core tablet and 30 minutes to coated tablet)

• The end-point of disintegration is defined in the USP/NF as follows: – "...that state where any residue

remaining on the screen is a soft mass having no palpably firm core"

• If the end-point is not reached after 30 minutes, terminate the test and record " > 30minutes ".

Disintegration

• Disintegration of tablets:Time required to fall through a sieve with a mesh of 2 mm

Conditions:

- tablet in water of 37°C- Up and down movement 55 mm- frequency 30/min

- requirement: < 15 min

55 mm

USP Disintegration Equipment

USP Disintegration Testing

• Basket-rack device

• Operates by reciprocating action

• Disintegration fluids (37C) water– simulated gastric fluid– simulated intestinal fluid– specialized buffer solution

• Record time required for disintegration

Factors Affecting Disintegration

• Addition of disintegrants

• Manufacturing method– Direct compression vs. wet granulation

• Pressure used for compression

• Tablet hardness

Dissolution

• The rate of absorption of the drug in the GIT is related to its rate of dissolution from the tablet.

• Rapid drug dissolution is important if a rapid onset of action is required.

Tablet Dissolution

• USP Apparatus I (Basket) and II (Paddle)– Round bottom flasks containing

dissolution media at 37C– Dosage form placed in the

basket or in the flask– Media mix by paddle or basket– Samples withdrawn at specific

time intervals and analyzed to determine concentration

• UV spectrophotometer• HPLC

Dissolution

USP dissolution apparatus II

Basket for USP dissolution apparatus I

Dissolution

• Dissolution: The time required for a certain drug fraction to dissolve from

the tablet. Different apparatus: e.g. paddle, cage, flow-through

The dissolution test• Conditions for the paddle method (USP method

II): – Medium: 900 ml (or 500 ml) 37 °C,

-0.01 M HCl,

-Phosphate buffer pH 4.0 - 7.0

-Half-chance: 2 hr 0.01 M HCl, subsequently pH 6.8

-Surfactants (Na-laurylsulfaat, Tween 80)

– Rotations: 50 tot 150 RPM

– Every 6 months FDA callibration tablets.

– Requirements depend on tablet type:• Immediate release: Q(80) < 45 min (30 min)• Slow release: at least 3 points: (burst, mean, end)• Sustained release: 2 punten (zero value, end value)

Tablets

Processing step

Direct Dry Wet

Raw material x x x

Weigh x x x

Screen x x x

Mix x x x

Compress (slug)

x

Wet mass x

Mill x

Dry x

Mill x x

Mix x x

Compress x x x

TABLET & CAPSULE ANALYTICAL TESTS

Parameter Hal yg hrs diperhatikan

KT - Kekerasan disesuaikan dg btk-ukuran

DT - Sesuai syarat pd monografi

Friabilita - 100 putaran

Tebal/ukuran - Disesuaikan dg jenis kemasan/mesin

pengemas

Stabilita fisik - T40RH 80% selama 3 bulan, penampilan msh

baik

Stabilita kadar - T40RH 80% slm 3 bulan memenuhi syarat