eksipien

EKSIPIEN SEDIAAN FARMASI @Dhadhang_WK Laboratorium Farmasetika Unsoed

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KANDUNGAN SEDIAAN OBAT R/ Bahan obat (Zat aktif)

Bahan tambahan (Eksipien)

SAFE EFFECTIVE ACCEPTABLE

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BAHAN AKTIF BAHAN AKTIF EKSIPIEN

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BAHAN BAKU: Semua bahan baik yang berkhasiat, maupun tidak berkhasiat, yang berubah maupun tidak berubah, yang digunakan dalam pengelolaan obat BAHAN AWAL: Semua bahan baku maupun bahan pengemas PRODUK ANTARA: Tiap bahan atau campuran bahan yang masih memerlukan satu atau lebih tahap pengolahan lebih lanjut untuk menjadi produk ruahan 25/03/2015

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PRODUK RUAHAN Tiap bahan olahan yang masih memerlukan tahap pengemasan untuk mejadi produk jadi PRODUK JADI Suatu produk yang telah melalui seluruh tahap proses pembuatan

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BAHAN BAKU

PRODUK ANTARA

ZAT AKTIF + EKSIPIEN

BAHAN AWAL BAHAN PENGEMAS

PRODUK RUAHAN

PRODUK JADI 25/03/2015

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PHYSICAL PROPERTIES dari BAHAN BAKU • BERLAKU UNTUK ZAT AKTIF DAN EKSIPIEN • CAKUPAN : - UKURAN PARTIKEL , DISTRIBUSI PARTIKEL - BENTUK PARTIKEL / KRISTAL - POLIMORFI , HIDRAT, SOLVAT - TITIK LEBUR , KELARUTAN - KOEFISIEN PARTISI, DISOLUSI - FLUIDITAS (SIFAT ALIR), KOMPAKTIBILITAS - PEMBASAHAN - PRODUKSI /FABRIKASI - KETERSEDIAAN FARMASETIK / HAYATI 25/03/2015

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KONTROL BAHAN AWAL: BAHAN OBAT DAN EKSIPIEN - UKURAN PARTIKEL, BENTUK PARTIKEL, KELARUTAN, TITIK LEBUR, KERAPATAN JENIS, DLL - KADAR ZAT AKTIF, DISOLUSI

- CARA PENGAMBILAN SAMPEL: METODE MILITARY STANDARD = Vn + 1 - TEMPAT PENGAMBILAN DI RUANG KHUSUS - SAMPEL DENGAN NOMER BATCH YANG TIDAK JELAS LANGSUNG DITOLAK

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AKIBAT PENANGANAN BAHAN BAKU YANG

TIDAK BAIK 1. KERUSAKAN BAHAN BAKU

2. PENGANGGURAN ALAT PRODUKSI 3. KEMUNDURAN PRODUKSI 4. KENAIKAN BIAYA OPERASIONAL

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EXCIPIENTS • ARE USED TO BRING DRUG(S) INTHE MOST SUITABLE DOSAGE FORMS • THEY SHOULD IMPROVES THE PROPERTIES OF THE DRUG IN THE DOSAGE FORMS • TO BRING THE DRUG IN THE MOST APPROPRIATE FORM TO THE OPTIMAL PLACE ABSORPTION AT THE RIGHT TIME AND THE RIGHT DOSE (INCUDING DRUG TARGETING) • TO IMPROVE DRUG STABILITY • TO MASK BITTER TASTE • TO IMPROVE PATIENT COMPLIANCE

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• Eksipien atau bahan penolong adalah materi yang terdapat dalam obat namun tidak memiliki efek farmakologi • Fungsinya sebagai pembawa atau pelarut zat aktif sehingga memungkinkan penyampaian obat. • Eksipien meningkatkan kualitas fisik obat dengan mempengaruhi transpor obat dalam tubuh, mencegah kerusakan sebelum sampai ke sasaran, meningkatkan kelarutan, dan bioavailabilitas, meningkatkan stabilitas obat, menjaga pH dan osmolaritas, menstabilkan emulsi, mencegah disosiasi zat aktif dan memperbaiki penampilan sediaan.

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Excipients

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Tujuan Penggunaan Eksipien 1. 2.

3.

4.

5.

Bahan pembantu selama proses pembuatan sedang berlangsung Mencegah, mendukung, atau meningkatkan stabilitas dan bioavailabilitas Membantu identifikasi produk Meningkatkan atribut lainnya seperti keamanan, efektivitas produk obat selama penyimpanan atau penggunaan Dan lain-lain...

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Persyaratan Eksipien 1. 2. 3. 4.

5. 6.

Inert Stabil secara fisik dan kimia Bebas mikroba perusak dan patogen Mendukung bioavailabilitas Tersedia dalam perdagangan Harga relatif murah

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Overview of excipients commonly used (particularly in oral dosage forms)

– Role of Key Solid Dose Excipients Diluents (fillers, bulking agents), Disintegrants, Binders, Lubricants, Glidants

– Role of Key Solution/Suspension Excipients Solvents/co-solvents , Buffering agents, Preservatives, Anti-oxidants, Wetting agents, Anti-foaming agents, Thickening agents, Sweetening agents, Flavouring agents, Humectants

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Drug products contain both drug substance (commonly referred to as active pharmaceutical ingredient or API) and excipients. Formulation of API with excipients is primarily to: – Ensure an efficacious drug product with desired properties and a robust manufacturing process

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The resultant biological, chemical and physical properties of the drug product are directly affected by the excipients chosen, their concentration and interactions with the API: – Consistency of drug release and bioavailability – Stability including protection from degradation – Ease of administration to the target patient population(s) by the intended route

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Excipients are sub-divided into various functional classifications, depending on the role that they are intended to play in the resultant formulation. Certain excipients can have different functional roles in different formulation types, e.g. lactose; widely used as: – a diluent, filler or bulking agent in tablets and capsules – a carrier for dry powder inhalation products (DPIs).

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Furthermore, individual excipients can have different grades, types and sources depending on those different functional roles…. 25/03/2015

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….for example, there are various grades of lactose commercially available that have different physical properties, e.g. flow characteristics & particle size distributions. This permits selection of what is considered the most suitable grade for a particular need……. – Wet Granulation: usually, finer grades of lactose are utilised as the binder is utilised more efficiently and this permits better mixing and granule quality. – Direct Compression: in contrast here, spray dried lactose is used as it flows better and is more compressible. …..And then for dry powder inhalers: crash-crystallisation fine-milled lactose with a coarser fraction for flow and a finer fraction to enhance API aerosolisation and delivery to the lungs

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In solid dosage forms, the key excipient types include: – – – –

Diluents, e.g. lactose, microcrystalline cellulose Disintegrants, e.g. sodium starch glycolate, croscarmellose sodium Binders, e.g. PVP, HPMC Lubricants, e.g. magnesium stearate Glidants, e.g. colloidal SiO2

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Diluents (Fillers) 

Bulking agent – E.g. to make a tablet weight practical for the patient: minimum tablet weight is typically ~50mg. Actual API doses can be as low as ~20µg, e.g. for oral steroids.

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Compression aid – Deforms and/or fragments readily to facilitate robust bonding in tablet compacts, e.g. microcrystalline cellulose.

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Good bulk powder flow….diluents have a strong influence – Good flow of bulk powders is very important in designing a robust commercial tablet product. Favoured combinations: Lactose is an excellent choice of filler in many respects but can exhibit poor flow characteristics, so is often combined with free-flowing microcrystalline cellulose in wet granulation formulations.

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Disintegrants 

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As an aid to de-aggregation of solid dosage forms. Disintegrants cause rapid break up (disintegration) of solid dosage forms upon exposure to moisture. Generally, disintegration is viewed as the first stage in the dissolution process, although dissolution does occur simultaneously with disintegration. Mode of action: – In many cases water uptake alone will cause disintegration, by rupturing the intraparticle cohesive forces that hold the tablet together and resulting in subsequent disintegration. – If swelling occurs simultaneously with water uptake, the channels for penetration are widened by physical rupture and the penetration rate of water into the dosage form increased.

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Binders 

Binders act as an adhesive to ‘bind together’ powders, granules and tablets to result in the necessary mechanical strength: – As a dry powder with other excipients in dry granulation (roller compaction, slugging) or as an extra-granular excipient in a wet granulation tablet formulation. – As a dry powder with other intra-granular excipients in wet granulation. When the granulating fluid is added, the binder may dissolve partially or completely to then exhibit adhesive binding properties in helping granules to form. – Most commonly in wet granulation, the binder is added already dissolved in the granulating fluid to enable a more effective and controllable granule formation.

– Water is the most common granulating fluid, very occasionally in a co-solvent system with, e.g. ethanol.

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Examples: – Dry binders: – Solution binders: – Soluble in water/ethanol mix: 25/03/2015

Microcrystalline cellulose, cross-linked PVP HPMC, PVP PVP 19

Lubricants 

Compression lubricants prevent adherence of granule/powder to punch die/faces and promote smooth ejection from the die after compaction: – Magnesium stearate is by far the most extensively used tableting lubricant – There are alternatives, e.g. stearic acid, sodium stearyl fumarate, sodium behenate – Lubricants tend to be hydrophobic, so their levels (typically 0.3 – 2%) need to be optimised:  Under-lubricated blends tend to flow poorly and show compression sticking problems  Over-lubricated blends can adversely affect tablet hardness and dissolution rate

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Lubricants can also be used when compression isn’t involved, e.g. – In powder blends for filling into capsules to prevent adherence of granule/powder to equipment surfaces and dosator mechanisms – Coating the surface of multi-particulate dosage forms (including intermediate product) to inhibit agglomeration of individual particles 25/03/2015

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Glidants Most commonly; colloidal silicon dioxide (traditionally, talc was used)  Good bulk powder flowability is especially important during high speed processing  Glidants improve flow by adhering to particles and so reducing inter-particulate friction – Most common in dry powder formulations, e.g. direct compression tablets – Can also be added to granules to improve flow prior to compression – NB: can get undesirable “flooding” if flow is too good 

Very low levels required (ca.