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PARENTERAL DOSAGE FORM

AnitaSukmawati

BagianFarmasetika,FakultasFarmasi

UniversitasMuhammadiyahSurakarta
MATERI:
PERTEMUAN TOPIK BAHASAN PENGAMPU

1 Introduction: drug selection and product early development. TN Saifullah

2 Biopharmaceutical consideration and support in candidate drug TN Saifullah

selection.

3 Product Optimization TN Saifullah

4 Product Optimization TNSaifullah

5 Product Optimization: application and case study TNSaifullah

6 Packaging for pharmaceutical Dosage Form TNSaifullah


7 Formulasiobatyangsukarlarutdalamair Erindyah

8 Oral Dosage Form: Solid Erindyah

9 Oral Dosage Form: Liquid Erindyah

10 Topical and Transdermal Dosage Form Erindyah

11 Parenteral Dosage form Anita Sukmawati

12 Parenteral Dosage form AnitaSukmawati


13 OphtalmicDosage Form AnitaSukmawati

12 Inhalation and Nasal Dosage Form AnitaSukmawati

15 EksipienFarmasi:aplikasieksipiendalamformulasi Anita Sukmawati

16 EksipienFarmasi:InteraksiEksipiendenganbahanaktif Anita Sukmawati

17 Product Stability Erindyah

18 Product Stability Erindyah


CAPAIAN PEMBELAJARAN:

• Mampumemahamimengenaitahapanpemilihankandiatuntukpengembanganobatmenjad
ibentuksediaanberdasarkanpertimbanganbiofarmasetika.
• Mampumelakukanoptimasiformulauntukprodukfarmasi.
• Mampumenjelaskanmengenaipengemasanuntuksediaanfarmasi.
• Mampumenjelaskanmengenaiformulasiobatyangsukarlarutdalamair.
• Mampumenjelaskanmengenaiformulasisediaanoral, parenteral,inhalasi,
nasaldanmata,topikaldantransdermal.
• Mampumenjelaskanmengenaieksipiendanpemilihaneksipienuntuksediaanfarmasi.
• Mampumenjelaskanmengenaicaraevaluasistabilitasprodukfarmasi.
PUSTAKA

• Gibson. M (Ed), 2009, PharmaceuticalPreformulationand Formulation: A Practical Guide

from Candidate Drug Selection to Commercial Dosage Form, Second

edition,InformaHealthcare, New York.

• Narang,AjitS,Boddu, Sai HS, (Eds), 2015, Excipient application in Formulation Design

and Drug Delivery, Springer.

• Williams III, Robert O., Alan B. Watts, and Dave A. Miller. Formulating poorly water

soluble drugs. AAPS Press, 2012.

• Yoshioka,Sumie, and Valentino J. Stella. Stability of drugs and dosage forms. Springer

Science & Business Media, 2000.

• Pustakalain yangrelevan
KONTRAK BELAJAR:

• Mulaikuliahtepatwaktu 10.30.13.00
• Terlibataktifdalamprosesbelajardanmengajar-
• Tidakdiperbolehkanadanyaplagiasi/contekanzero point
punishment(pemberiannilainol)
• ……………………………………………………
• ……………………………………………………...
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BAHAN KULIAH:

• Dapatdiunduhmelaluischoology.com

• Login/ sign inmenggunakanusernamedanpassword

• Joindengankelas:

FF-TeknologiFarmasidanRancanganFormula:Gasal2018-2019

• Access code:HBFH7-73VTS
PARENTERAL DOSAGE FORM:

• Non enteral or non Oral DDS


• Common routes for parenteral: IV, SC, IM, implants
• The primary route for peptide and protein drug.
• Formulations including: solutions, emulsion, suspension, liposome
and solid implant.
STANDAR KUALITAS PRODUK PARENTERAL:
CLASSIFICATION OF INJECTABLE PARENTERAL (USP)

• Small volume parenteral (SVP): less than 100 ml


•For bolus administration
•Can be administered with LVP.
•Administered through SC (< 1.5 ml) or IM (not more than 2 ml)
• Large Volume Parenteral (LVP): more than 100 ml
• For infusion administration

• Formulation of Parenteral product: depend on solubility administration


volume and concentration.
REQUIREMENT FOR PARENTERAL DRUG:

• pH
• Tonicity
• Choice of Excipients
• Sterility
pH Consideration:

• pH should be close to physiological pH 7.4


• Wide range pH can be tolerated if there is a rapid blood dilution within the
body.

• IM and SC route  slow blood dilution  pH should be arrange between 3-


11 (IM) and 3-6 (SC Route)

• Slightly acidic pH sometimes is needed  stability requirement, usually pH


3-9.

•pH less than 3  induce pain and phlebitis


•pH more than 9  tissue necrosis.
pH Consideration:

• Buffer may be required to


control pH between
maximum stability and
Solubility.
• Typically buffer concentration
use is 10-100mMol/L
TONICITY CONSIDERATION:

• Parenteral Dosage Form should be isotonic (osmolarities280-290mOsm/L).


• Tonicity is essential for LVP, not for SVP.
• Hypertonic is more preferable than hypotonic
• Hypotonic solution can be easily adjusted using excipient to
raiseosmolarity.
• Excipients can be used to raiseosmolarity:
•Sodium chloride.
•Manitol
•Dextrose
Choice of Excipients:

• Some literatures can be used for excipients


• Requirement for excipient in parenteral dosage form:
•Acceptable within the formulation
•In injectable grade limited for endotoxin
STERILITY CONSIDERATION:

• Sterility an absolute requirement for parenteral product.


• Choose the appropriate method for sterilization and filter.
• Method for sterilization:
•Moist heat sterilization
•Filtration  0.2 micron filter
•Gamma-irradiation
• Preservation should not be included in parenteral formulation, unless for
multiple dose product.
FORMULASI SEDIAAN PARENTERAL
PERTIMBANGAN DALAM FORMULASI:

• Pemilihanbahanpembawa: aqueous, non aqueous, co-solvent.

• Bahantambahan: buffer,antioksidant,antimikroba, chelating agent,pengaturtonisitas.

• Pemilihanbahanpengemastermasukbahanpenutup.
PEMILIHAN BAHAN PEMBAWA:

• Sebagianbesarprodukparenteralmenggunakanpembawaaqueous,tetapiadasebagianoba

t-

obatanyangakanmengalamihidrolisisjikaterkenaairperlupertimbanganpembawayangt

epat.

• Kelarutanbahanobatmelibatkaninteraksidipolantarabahanpadat/solutdengansolvent.Jika

strukturpelarutmenyerupaisolvent,makabahanpadat/solutakanmudahlarutkonsep“like

dissolve like”.

• Sifatmelarutkansuatupelarutdapatdilihatdarihargadielectric constant (DC).

•DCtinggi:melarutkanbahanpolardanionic
•DCrendah:melarutkanbahannon polar
HARGA DC BERBAGAI PELARUT DAN HUBUNGAN HARGA DC DENGAN

KELARUTAN:
Contoh:

• SuatuinjeksiakandibuatdenganhargaDC 60.Pelarutyangdipilihadalah:
•Air, DC 78.5
•PEG 400, DC 12.5
•Ethanol, DC 24.3
• Ethanol yangdigunakanuntukmelarutkanobatadalah10%.
• HitungpersentasePEG 400danair yangdigunakandalamformulasi!
• Jumlahair yangdigunakanuntukmelarutkanobat,misalX,maka:
•100.60 = (10).(24.3) + (x) (78.5) + (90-x) (12.5)
•X = 73.5%
• Komposisipelarutyangdigunakanadalah: Ethanol 10%, PEG 400 16.5%danair 73.5%
PEMILIHAN BAHAN TAMBAHAN:

• Bahantambahan: buffer,

antioxidant,antimikroba,pengaturtonisitas,peningkatkelarutan,surfaktandapatdigunak

anuntukmeningkatkanmutuproduk.

• Beberapabahantambahanjustrukadangmenghasilkandampakyangnegatif,misalpenurun

ankelarutanataustabilitasobat.
PEMILIHAN CONTAINER UNTUK SEDIAAN PARENTERAL:

• Fungsikontaineruntukprodukparenteral:

• Memfasilitasiprosespembuatan

• Memproteksiproduk:mempertahansterilitasdanbebaspirogen

• Mempermudahpemeriksaan

• Mempermudahpenyimpanandanproses shipping

• Mempermudahpemakaiansecaraklinis

• Kontainerdianggapsebagaibagianyang integraldarisediaanparenteral.
CONTAINER FOR PARENTERAL PRODUCT

GLASS CONTAINER PLASTIC PACKAGING

• Memilikidayaproteksiyanglebihren
• Bersifatinert.
• Impermeablesehinggasulitterkontamina dahdengangelas.
si
• Transparan,sehinggamudahdiguna
• Relatifstabildalamprosessterilisasipana
sdandepirogenisasi. kandalampengontrolanproduk.
• Mudahrusakdalamprosestransportasiat
audalamprosespenyimpanan. • Tidakmudahrusakdalamprosespeny
• Relatifmahal. impanandantransportasi.
PARENTERAL DOSAGE FORMS:

• SOLUTION

• SUSPENSION

• EMULSION

• DRY POWDER
SOLUTION:

• Dissolving drug and excipientadjusting pH  sterilization


• Sterilization solution:
•Filtering
•Aseptic filling
•Autoclaving
SUSPENSION:

• Very difficult to formulate and produce


• Need critical rheological properties from container to syringe, from syringe
to vein.
• Components: active ingredients, aqueous vehicle, surfactant for wetting,
preservative, buffers
• Vehicle for suspension: vegetable oil or aqueous vehicle.
SUSPENSION:
SUSPENSION:
EMULSION

• Rarely used as parenteral product as it need stability requirement.


• Very limited selection of stabilizer and emulsifier.
• Size of droplet should less than 1 micron to prevent emboli in blood vessel.
• Parenteral emulsion can be use for:
• W/o emulsion given subcutaneously
• o/w sustained release depot preparation,given subcutaneously
• o/wnutrienemulsion, given intravenously.
• Commonly in o/w emulsion.
DRY POWDER:

• To prevent intrinsic instability in aqueous medium, to be reconstituted


before use.
• Method of preparation:
•Freeze drying
•Asepticcrystalizationand dry powder filling
•Spray drying.
DRY POWDER:
TUGAS
TUGAS

• Susunlahpresentasiberdasarkanpembagianmateriterlampir.

• Pustakadapatberasaldariyangdiberikan,atausumberlain yangrelevan.

• Waktupengerjaaan:maksimal27 Sept 2018, jam 14.00

• Durasipresentasiuntuktiapkelompokadalah15menit.
STRATEGIES FOR FORMULATING POORLY
SOLUBLE DRUG
pH manipulation

• pH manipulation is needed to achieve adequate solubility in salt compound.

• There is a possibility for precipitation.

Cosolvent

• Cosolvent:glycerin, ethanol,propilenglycol,polyethylenglycol, N-N dimethylacetamide.


• The concentration ofcosolventis depend on route and rateadministartion.
COSOLVENCY:
SURFACTANS:

• Generally used in parenteral product in very low concentration (0.05%).


• Prevent aggregation in parenteral product.
COMPLEXING AGENTS:

• Complexingagent: molecules that have ability to form soluble


complex with insoluble drug.
• Example:cyclodextrin
• Alpha-cyclodextrin can induce nephrotoxicity
• Hydroxypropyl-beta-cyclodextri low toxicity and adequate
solubility.
STRATEGIES FOR FORMULATING UNSTABLE
MOLECULES
WATER REMOVAL:

• Hydrolysis common problem in parenteral formulation.


• Removal of water bylyophilization
• Excipient inlyophilizationas bulking agent:
• Mannitol :crystalinematerial, easy to freeze dry and has aesthetic

properties.

• Sucrose: amorphous material, improve stability, has

longlyophilizationcycle.
USE OF EXCIPIENTS:

• Excipient may be useful in preventing chemical and physical instability


• To prevent oxidation remove the oxygen from formulation.
• Prevent oxidation:
• Use antioxidant: ascorbic acid (1%), sodiummetabisulfit(0.3%).
• purging with nitrogen
• Use metalchelator: EDTA (0.05%)
NON AQUEOUS FORMULATION

• Using nonaquoeousvehicle
• Use an oil-in-water emulsion
EXCIPIENT IN PARENTERAL FORMULATION
FungsiEksipiendalamsediaanparenteral:

• Untukmeningkatkankelarutanobat.

• Meningkatkanstabilitasobat.

• Memberikanperlindunganterhadappertumbuhanmikroba.

Eksipiendapatmemberikanpengaruhyan

gsignifikanpadasuatuprodukobat
EKSIPIEN DALAM SEDIAAN PARENTERAL
IN VITRO AND IN VIVO TESTING METHOD
IN VITRO PRECIPITATION: Haemolysis

• Visual test
• In vivo test measuring free
• Flow through method: detected using
haemoglobin in blood and urine.
spectrophotometer.
PHLEBITIS PAIN

• Inflammation in vein wall caused by • Cause by long resistance of


particulate matter formulation at injection site.

• In vitro precipitation test • Evaluation using

rabbitlessionmodel