Introduction to Introduction to COMPOUNDING COMPOUNDING PRACTICESPRACTICES

By Gunawan Setiyadi, S.Si., By Gunawan Setiyadi, S.Si., Apt.Apt.

@ta collection@ta collection

PharmacistsPharmacists

Profesi yang unikProfesi yang unikTerlatih dalam ilmu alam, fisik, dan Terlatih dalam ilmu alam, fisik, dan

medismedisMemiliki pengetahuan dan Memiliki pengetahuan dan

keterampilan yang tidak tergantikan keterampilan yang tidak tergantikan oleh profesi lainoleh profesi lain

Perannya: meracik (Perannya: meracik (compoundingcompounding) dan ) dan menyerahkan (menyerahkan (dispensingdispensing) obat, ) obat, konseling pasien, meminimalkan konseling pasien, meminimalkan medication errors, meningkatkan medication errors, meningkatkan kepatuhan pasien, monitoring drug kepatuhan pasien, monitoring drug therapy, and meminimalkan biaya obattherapy, and meminimalkan biaya obat

Apoteker dalam praktik Apoteker dalam praktik compoundingcompounding

Fungsi compounding adl utk Fungsi compounding adl utk mengindividualisasi terapi pasien mengindividualisasi terapi pasien

Keahlian apoteker digunakan utk Keahlian apoteker digunakan utk menyesuaikan besaran dosis, frekuensi menyesuaikan besaran dosis, frekuensi pemberian, dan bahkan bentuk sediaan pemberian, dan bahkan bentuk sediaan utk meningkatkan kepatuhan pasien.utk meningkatkan kepatuhan pasien.

Apoteker harus paham akan pilihan-Apoteker harus paham akan pilihan-pilihan terapi obat yg bisa diberikan pilihan terapi obat yg bisa diberikan dengan praktik compounding.dengan praktik compounding.

……..

Apoteker bertanggung jawab utk Apoteker bertanggung jawab utk melayani pasien mrk dan meracik melayani pasien mrk dan meracik sediaan obat yg diresepkan dlm sediaan obat yg diresepkan dlm kerangka praktik profesional.kerangka praktik profesional.

Meracik obat (steril atau nonsteril) Meracik obat (steril atau nonsteril) merupakan hak dan kewajiban merupakan hak dan kewajiban apoteker utk memenuhi kebutuhan apoteker utk memenuhi kebutuhan khusus pasien.khusus pasien.

Materi :Materi :

DefinisiDefinisi The technical aspects and economic impact of The technical aspects and economic impact of

compoundingcompounding Facilities & equipmentFacilities & equipment IngredientsIngredients Steps in the compounding processSteps in the compounding process Packaging & labelingPackaging & labeling Stability, expiration and beyond-use datingStability, expiration and beyond-use dating Records and reportsRecords and reports

DefinisiDefinisi Compounding is the act of preparing, mixing, Compounding is the act of preparing, mixing,

assembling, packaging, and/or labelling of a assembling, packaging, and/or labelling of a drug or device as the result of a practitioner’s drug or device as the result of a practitioner’s Prescription Drug Order or initiative based on Prescription Drug Order or initiative based on the practitioners-patient-pharmacist the practitioners-patient-pharmacist relationship in the course of professional relationship in the course of professional practice, or for the purpose of, or as an practice, or for the purpose of, or as an incident to, research, teaching, or chemical incident to, research, teaching, or chemical analysis and not for sale or dispensing.analysis and not for sale or dispensing.

Compounding also includes the preparations of Compounding also includes the preparations of drugs or devices in anticipations of drugs or devices in anticipations of prescriptions drug orders based on routine, prescriptions drug orders based on routine, regularly observed prescribing patterns.regularly observed prescribing patterns.

[National Association of Boards of Pharmacy][National Association of Boards of Pharmacy]

Produksi sediaan obatProduksi sediaan obat

Manufacturing Manufacturing

manufactured drug productmanufactured drug product

expiration date, biasanya dlm expiration date, biasanya dlm tahuntahun

Extemporaneous compoundingExtemporaneous compounding

compounded drug preparationcompounded drug preparation

beyond-use date, biasanya dlm beyond-use date, biasanya dlm hari atau bulanhari atau bulan

Manufacturing vs Manufacturing vs CompoundingCompounding

ManufacturingManufacturing Mass productionMass production Fixed-dose productsFixed-dose products

No triad relationship No triad relationship physician-patient-physician-patient-pharmacist pharmacist

Market autorizationMarket autorization Stabilitas terukurStabilitas terukur Expiration dateExpiration date cGMP, CPOB, ISOcGMP, CPOB, ISO

CompoundingCompounding Limited preparationLimited preparation Individualized Individualized

prescription/therapyprescription/therapy Triad relationship Triad relationship

physician-patient-physician-patient-pharmacistpharmacist

Off-labelOff-label Stabilitas ???Stabilitas ??? Beyond-use dateBeyond-use date Standar kompetensi Standar kompetensi

apoteker (?) etika (?)apoteker (?) etika (?)

3 types of compounded 3 types of compounded prescriptions :prescriptions :

Isolated prescriptionsIsolated prescriptionsRoutine prescriptionsRoutine prescriptionsBatch prescriptionsBatch prescriptions

Compounding activitiesCompounding activities

The preparation of suspensions, topicals, The preparation of suspensions, topicals, and suppositoriesand suppositories

The conversion of dose (e.g. oral to rectal, The conversion of dose (e.g. oral to rectal, injection to oral)injection to oral)

The conversion of a dosage form into The conversion of a dosage form into anotheranother

The preparation of select dosage forms from The preparation of select dosage forms from bulk chemicalbulk chemical

The preparation of intravenous admixtures The preparation of intravenous admixtures and parenteral nutrition solutionsand parenteral nutrition solutions

……..

The preparation of paediatric dosage The preparation of paediatric dosage forms from adult dosage formsforms from adult dosage forms

The preparation of radioactive The preparation of radioactive isotopesisotopes

The preparation of cassettes, syringe The preparation of cassettes, syringe and other devices with drugs for and other devices with drugs for administration in the home settingadministration in the home setting

Etc.Etc.

Reasons for compoundingReasons for compounding

The impact of home healthcareThe impact of home healthcareNeeds for individualized drug therapyNeeds for individualized drug therapyUnavailable drug productsUnavailable drug productsOrphan drugsOrphan drugsVeterinary compoundingVeterinary compoundingBiotechnology-derived productsBiotechnology-derived products

““It almost seems unvelievable that, as It almost seems unvelievable that, as we in health care become more aware we in health care become more aware that patients are ‘individuals’, respond that patients are ‘individuals’, respond as ‘individuals’, and must be treated as as ‘individuals’, and must be treated as ‘individuals’, some health care ‘individuals’, some health care providers appear to be grouping providers appear to be grouping patients into ‘categories’ for treatment patients into ‘categories’ for treatment and ‘categories’ for reimbursement and ‘categories’ for reimbursement from third-payers or ‘categories’ for from third-payers or ‘categories’ for determining levels of care in managed determining levels of care in managed care organizations.”care organizations.”

Should every pharmacist Should every pharmacist compound?compound?

Legally, any pharmacist is qualified Legally, any pharmacist is qualified to compoundto compound

Technically, only properly trained Technically, only properly trained pharmacists should be involved in pharmacists should be involved in pharmaceutical compounding.pharmaceutical compounding.

Should every pharmacist Should every pharmacist compound?compound?

To be capable of meeting the special or To be capable of meeting the special or advanced needs of today’s patients, whether advanced needs of today’s patients, whether human or animal, a compounding pharmacist human or animal, a compounding pharmacist must:must: Have access to the most recent information availableHave access to the most recent information available Maintain an inventory and provide for proper storage Maintain an inventory and provide for proper storage

of drugs and flavoring agents and be capable of of drugs and flavoring agents and be capable of obtaining any chemical within a reasonable timeobtaining any chemical within a reasonable time

Be dedicated to pharmacy and willing to put forth the Be dedicated to pharmacy and willing to put forth the necessary financial and time investmentnecessary financial and time investment

…….. Have the appropriate physical facilities and Have the appropriate physical facilities and

equipment to do the job right (the extent and type of equipment to do the job right (the extent and type of compounding may be determined or limited by the compounding may be determined or limited by the facility)facility)

Be commited to lifelong learning and continuing Be commited to lifelong learning and continuing education, since a major advantage of compounded education, since a major advantage of compounded prescriptions is that they provide treatments that are prescriptions is that they provide treatments that are new, undeveloped, and often not commercially new, undeveloped, and often not commercially available.available.

Have a willingness to tear down walls and build Have a willingness to tear down walls and build bridges to share experiences with others for the good bridges to share experiences with others for the good of all.of all.

The technical aspects and The technical aspects and economic impact of compoundingeconomic impact of compounding

1.1. Is the product commercially available in Is the product commercially available in the exact dosage form, strength and the exact dosage form, strength and packaging?packaging?

2.2. Is the prescription rational concerning the Is the prescription rational concerning the ingredients, intended use, dose and ingredients, intended use, dose and method of administration?method of administration?

3.3. Are the physical, chemical and therapeutic Are the physical, chemical and therapeutic properties of the individual ingredients properties of the individual ingredients consistent with the expected properties of consistent with the expected properties of the ordered drug product?the ordered drug product?

Technical considerations forTechnical considerations forcompounding a prescription:compounding a prescription:

Technical considerations forTechnical considerations forcompounding a prescription:compounding a prescription:

1.1. Will this compounded product satisfy the Will this compounded product satisfy the intent of the prescribing physician and meet intent of the prescribing physician and meet the needs of the patient?the needs of the patient?

2.2. Is there an alternative (e.g. different dosage Is there an alternative (e.g. different dosage form, different route of administration) by form, different route of administration) by which the patient will receive a benefit?which the patient will receive a benefit?

3.3. Is there a bonafide prescriber-pharmacist-Is there a bonafide prescriber-pharmacist-patient relationship?patient relationship?

4.4. Can ingredient identity, quality and purity Can ingredient identity, quality and purity be assured?be assured?

5.5. Does the pharmacist have the training and Does the pharmacist have the training and expertise required to prepare the expertise required to prepare the prescription?prescription?

Technical considerations forTechnical considerations forcompounding a prescription:compounding a prescription:

1.1. Are the proper equipment,supplies and Are the proper equipment,supplies and chemicals or drugs available?chemicals or drugs available?

2.2. Is there a literature reference that might Is there a literature reference that might provide information on use, preparation, provide information on use, preparation, satbility, administration and storage of the satbility, administration and storage of the product?product?

3.3. Can the pharmacist perform the necessary Can the pharmacist perform the necessary calculations to prepare the product?calculations to prepare the product?

4.4. Can the pharmacist project a reasonable and Can the pharmacist project a reasonable and rational beyond-use date for the rational beyond-use date for the prescription?prescription?

Technical considerations forTechnical considerations forcompounding a prescription:compounding a prescription:

1.1. Can the pharmacist willing to complete the Can the pharmacist willing to complete the necessary documentation to prepare the necessary documentation to prepare the product?product?

2.2. What procedure are in place for investigating What procedure are in place for investigating and correcting failures?and correcting failures?

3.3. How long will the patient be using the How long will the patient be using the product and is the expected duration of product and is the expected duration of therapy consistent with an appropriate therapy consistent with an appropriate expirationexpiration

4.4. Alternatively, should the product be Alternatively, should the product be prepared in small quantities and dispensed prepared in small quantities and dispensed to the patient in short intervals?to the patient in short intervals?

5.5. Does the patient have the necessary storage Does the patient have the necessary storage facility, if required, to ensure the potency of facility, if required, to ensure the potency of the product until its beyond-use date?the product until its beyond-use date?

Economic considerations forEconomic considerations forcompounding a prescription:compounding a prescription:

1.1. The pharmacist’s compensation for the The pharmacist’s compensation for the serviceservice

2.2. The impact of the service on health care costThe impact of the service on health care cost

The pharmacist’s The pharmacist’s compensation for the servicecompensation for the service

Pharmaceutical compounding is a cognitive service.Therefore, appropriate reimbursement is justified.

The pricing of a compounded prescription should The pricing of a compounded prescription should take into consideration:take into consideration:

Pharmacodynamic/pharmacotherapeutic Pharmacodynamic/pharmacotherapeutic decision makingdecision making

Formulation expertiseFormulation expertise The time involvesThe time involves Reimbursement for materialsReimbursement for materials

Compounding prescription can be one way of Compounding prescription can be one way of lowering the cost of drug therapy : enable lowering the cost of drug therapy : enable patient to afford the drug therapy, divide patient to afford the drug therapy, divide commercial product into smaller units.commercial product into smaller units.

Facilities & EquipmentFacilities & Equipment

The compounding area should be The compounding area should be located sufficiently away from routine located sufficiently away from routine dispensing , counseling functions and dispensing , counseling functions and high traffic areashigh traffic areas

The area should be isolated from The area should be isolated from potential interruptions, chemical potential interruptions, chemical contaminants and sources of dust and contaminants and sources of dust and particulate matterparticulate matter

Proper temperature & humidity controlProper temperature & humidity control Well lightedWell lighted

Facilities & EquipmentFacilities & Equipment

Work surface should be smooth and Work surface should be smooth and cleanclean

The equipment needed to compound a The equipment needed to compound a drug product depends upon the drug product depends upon the particular dosage form requested.particular dosage form requested.

Weighing equipmentWeighing equipment Measuring equipmentMeasuring equipment Compounding equipment: mortar & Compounding equipment: mortar &

pestles,spatula,filter, a source of heat pestles,spatula,filter, a source of heat paper,beaker,refrigerator & freezerpaper,beaker,refrigerator & freezer

PERSONNELPERSONNEL Include : pharmacist and supportive personnel Include : pharmacist and supportive personnel

engaged in any aspect of the compounding engaged in any aspect of the compounding procedureprocedure

Training:Training:1.1. Proper use of compounding equipmentProper use of compounding equipment2.2. Pharmaceutical techniques needed for preparing Pharmaceutical techniques needed for preparing

compounded dosage formcompounded dosage form3.3. Properties of dosage formProperties of dosage form4.4. Literature in which information on stability, solubilityLiterature in which information on stability, solubility5.5. Handling of nonhazardous and hazardous materials Handling of nonhazardous and hazardous materials

in the work areain the work area6.6. Pharmaceutical calculationsPharmaceutical calculations7.7. Use and interpretation of chemical and Use and interpretation of chemical and

pharmaceutical symbolspharmaceutical symbols

Facilities & EquipmentFacilities & Equipment

INGREDIENTSINGREDIENTS

Selection may depend on the Selection may depend on the dosage form to be compoundeddosage form to be compounded

In most cases, the prescriber In most cases, the prescriber specifies a particular dosage formspecifies a particular dosage form

Sometimes, the prescriber relies Sometimes, the prescriber relies on the pharmacist to decide on an on the pharmacist to decide on an appropriate formappropriate form

Factor to consider in selecting the Factor to consider in selecting the dosage form include:dosage form include:

1.1. Physical & chemical characteristics of the Physical & chemical characteristics of the active ingredientactive ingredient

2.2. Possible routes of administration that will Possible routes of administration that will produce the desired therapeutic effect (oral produce the desired therapeutic effect (oral or topical)or topical)

3.3. Patient characteristic (age, level of Patient characteristic (age, level of consciousness, ability to swallow a solid consciousness, ability to swallow a solid dosage form)dosage form)

4.4. Specific characteristics of the disease being Specific characteristics of the disease being treatedtreated

5.5. Comfort for the patientComfort for the patient

6.6. Ease or convenience of administrationEase or convenience of administration

IngredientsIngredients

If ingredients are If ingredients are liquidliquid

Should consider Should consider compounding liquid compounding liquid dosage form dosage form (solution,syrup,elixir)(solution,syrup,elixir)

If ingredients are If ingredients are crystal, powdercrystal, powder

Compounding dry Compounding dry dosage form (divided dosage form (divided powder,capsul)powder,capsul)

If ingredients are If ingredients are both liquid & dry both liquid & dry formform

Compounding Compounding suspension, elixir,syrupsuspension, elixir,syrup

Note:Note:

Extended release or delayed Extended release or delayed release products should not be release products should not be crushed.crushed.

Preservative & excipients may Preservative & excipients may affect stability and bioavailability affect stability and bioavailability so the presence should not be so the presence should not be ignoredignored

Steps in the compounding Steps in the compounding processprocess

PreparatoryPreparatoryCompoundingCompoundingFinal checkFinal checkSign offSign offClean upClean up

PreparatoryPreparatory

1.1. Judging the suitability of the prescription in terms Judging the suitability of the prescription in terms of its safety and intended use and the dose for of its safety and intended use and the dose for the patientthe patient

2.2. Performing the calculations to determine the Performing the calculations to determine the quantities of the ingredients neededquantities of the ingredients needed

3.3. Selecting the proper equipment and making sure Selecting the proper equipment and making sure it is cleanit is clean

4.4. Donning the proper attire and washing handsDonning the proper attire and washing hands

5.5. Cleaning the compounding area and the Cleaning the compounding area and the equipment, if necessaryequipment, if necessary

6.6. Assembling all the necessary Assembling all the necessary materials/ingredients to compound and package materials/ingredients to compound and package the prescriptionthe prescription

CompoundingCompounding

1.1. Compounding the prescription Compounding the prescription according to the formulary record according to the formulary record or the prescription using or the prescription using techniques according to the art techniques according to the art and science of pharmacyand science of pharmacy

Final checkFinal check

2.2. Checking, as indicated, the weight Checking, as indicated, the weight variation, adequacy of mixing, clarity, variation, adequacy of mixing, clarity, odor, color,consistency and pHodor, color,consistency and pH

3.3. Entering the information in the Entering the information in the compounding logcompounding log

4.4. Labeling the prescriptionLabeling the prescription

Sign offSign off

1.1. Signing and dating the prescription Signing and dating the prescription affirming that all of the indicated affirming that all of the indicated procedures were carried out to ensure procedures were carried out to ensure uniformity, identity, strength, quantity uniformity, identity, strength, quantity and purityand purity

Clean upClean up

1.1. Cleaning and storing all Cleaning and storing all equipmentequipment

2.2. Cleaning the compounding areaCleaning the compounding area

Packaging & LabelingPackaging & Labeling

Container for compoundedContainer for compoundedproducts:products:a.a. should be appropriate for the should be appropriate for the

dosage form compoundeddosage form compoundedb.b. should not interact physically or should not interact physically or

chemically with the product (so chemically with the product (so as to alter strength, quality, as to alter strength, quality, purity )purity )

Stability, expiration and Stability, expiration and beyond-use datingbeyond-use dating

The USP-NFThe USP-NF defines stability as the defines stability as the extent to which a dosage form extent to which a dosage form retains, within specified limits and retains, within specified limits and throughout its period of storage throughout its period of storage and use, the same properties and and use, the same properties and characteristics that possessed at characteristics that possessed at the time of its preparation.the time of its preparation.

Stabilitas obat produk manufaktur Stabilitas obat produk manufaktur

tercermin dalam expiration date Expiration date umumnya adalah tanggal

ketika obat telah terdegradasi hingga 90% Expiration date merupakan hasil dari uji

stabilitas berdasarkan kinetika degradasi kimiawi senyawa aktif

Apoteker hrs mengelola obat produk manufaktur sesuai instruksi pd label, terutama aturan penyimpanan, dan menyampaikan informasi tsb kepada pasien saat dispensing untuk penyimpanan/penanganan oleh pasien.

Expiration date

USP 27 (2004) “The expiration date identifies the time

during which the article may be expected to meet the requirements of the Pharmacopeial monograph, provided it is kept under the prescribed storage conditions.”

“The expiration date limits the time during which the article may be dispensed or used.”

“Where an expiration date is stated only in terms of the month and the year, it is a representation that the intended expiration date is the last day of the stated month.”

Stabilitas sediaan racikan (compounded preparation)

Beyond-use date

USP “the dispenser shall place on the label of the

prescription container a suitable beyond-use date to limit the patient’s use of the article based on any information supplied by the manufacturer and the General Notices and Requirements of this Pharmacopeia. The beyond-use date placed on the label shall not be later than the expiration date on the manufacturer’s container”

Beyond-use date is defined as that Beyond-use date is defined as that date after which a dispensed date after which a dispensed product should no longer be used product should no longer be used by a patientby a patient

= discard-after date (= discard-after date (the date after which a compounded preparation should be discarded).

Pertimbangan dalam menetapkan beyond-use date

Sifat obat dan kinetika degradasinya Wadah yang digunakan untuk

mengemas obat tersebut Kondisi penyimpanan sediaan Lama terapi Expiration date produk komersial

serupa, sbg pedoman, jika zat aktifnya USP/NF substance

Literatur terpublikasi Informasi dari produsen: printed doc,

telepon

Permasalahan dlm penetapan beyond-use date Tidak tersedianya data stabilitas formula

sediaan racikan (compounded) Banyak ketidakstabilan tidak bisa terdeteksi

tanpa peralatan analitik. Berbeda dg inkompatibilitas yg bisa teramati scr visual.

Formula racikan mungkin berbeda dg produk pabrik (beda konsentrasi, diluen dan eksipien lain, bahan pengemas) shg beyond-use date tidak bisa begitu saja diekstrapolasi atau diestimasi dari expiration date.

USP Chapter <795>“In the absence of stability information that is applicable to a specific drug andpreparation, the following maximum beyond-use dates are recommended for non sterile compounded drug preparations that are packaged in tight, light-resistant containers and stored at controlled room temperature unless otherwiseindicated.

For nonaqueous Liquids and Solid Formulations (Where the manufactured drugproduct is the source of active ingredient)---The beyond-use date is not later than25% of the time remaining until the product’s expiration date or 6 months, which-ever is earlier.(Where a USP or NF substance is the source of active ingredient)---The beyond-use date is not later than 6 months.

For Water-Containing Formulations (prepared from ingredients in solid form)---The beyond-use date is not later than 14 days when stored at cold temperature.

For All Other Formulations---The beyond-use date is not later than the intendedduration of therapy or 30 days, whichever is earlier. These beyond-use date limits may be exceeded when there is supporting valid scientific stability informa-tion that is directly applicable to the specific preparation (i.e. the same drug con-tcntration range, pH, excipients, vehicle, water content, etc.”

Contoh:Diazepam tablet digerus dan

dimasukkan ke dalam kapsul. Jika tablet tsb mempunyai ED 1 tahun dari saat penggerusan (compounding), BUD maksimum diaz dlm kapsul adl 3 bulan (25% dari 1 tahun). Dengan asumsi, kapsul tsb diberikan dan disimpan di dlm wadah tertutup rapat (tight), kedap cahaya, di dalam temperatur ruang yg terkontrol.

ContohJika kapsul diazepam diracik dengan

menggunakan serbuk diazepam murni USP, BUD maksimum adl 6 bulan, dg asumsi ED serbuk diaz lebih dari 6 bulan.

Jika ED diaz kurang dari 6 bulan, maka BUD kapsul diaz tsb diperpendek. Misalnya, ED diaz = 4 bulan, maka BUD kapsul diaz adl 1 atau 2 bulan.

Contoh Jika tablet komersial yang digerus atau

serbuk murni digunakan utk membuat suspensi diazepam dg medium air, maka BUD maksimum adalah 14 hari.

BUD tsb berlaku dg asumsi suspensi tsb disimpan di tempat dingin (refrigerator)

Utk diaz tdp banyak laporan penelitian ttg formulasinya dlm btk suspensi. Salah satu formulasi tsb stabil sampai 60 hari.

Jika formula tsb digunakan maka BUD bisa diperpanjang sesuai dg laporan penelitian tsb.

ContohJika tablet komersial yg digerus atau

serbuk murni digunakan utk membuat suppositoria diazepam, maka tdp pilihan BUD:3 bulan (jika menggunakan tablet yg

diserbuk) krn produk nonaqueous6 bulan (jika menggunakan serbuk obat

murni) krn produk nonaqueous3 hari atau lamanya terapi krn

“bentuk sediaan lainnya”

Tipe-tipe stabilitas obat

Menurut USP Chemical: Each active ingredient retains its

chemical integrity and labeled potency, within the specified limits.

Physical: The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability are retained.

Microbiological Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits.

Therapeutic: The therapeutic effect remains unchanged.

Toxicological: No significant increase in toxicity occurs.

Potential adverse effect of instability in pharmaceutical products:Hilang/berkurangnya zat aktifNaiknya konsentrasi zat aktifPerubahan bioavailabilitas (perubahan

F) Hilangnya keseragaman kandunganBerubahnya status mikrobiologisLoss of pharmaceutical elegance and

patient acceptabilityFormation of toxic degradation

products

Stabilitas kimiawi

Sifat kimia obat adalah sifat yang termanifestasi oleh struktur molekul obat tersebut.

Jika terjadi perubahan kimia, molekul obat asli tidak ada lagi (hilang/berkurang)

Stabilitas Kimiawi

Kriteria menurut USP Chapter <1191>“Each active ingredient retains its

chemical integrity and labeled potency, within the specified limits.”

Dekomposisi Kimiawi (Chemical Decomposition)Hilangnya obat aktif (loss of active)Hilangnya pharmaceutical elegance

(kepatutan farmasetis) Terbentuknya produk yang toksik

Hilangnya zat aktif (loss of active): Pada umumnya obat dikatakan tidak

berkulitas bila telah mengalami penurunan zat aktif lebih dari 10% (kadar zat aktif tinggal 90%-nya)

Hilangnya zat aktif bisa berakibat pada terjadinya terapi yang suboptimal

Kurva degradasi obat

Hilangnya “pharmaceutical elegance” (kepatutan farmasetis), seperti:

timbul bau tidak enak, tengikperubahan warna, akibat reaksi

kimiaproblema rasa, dari inert menjadi

asam

Hilangnya pharmaceutical elegance bisa berpengaruh pada kepatuhan pasien dan akhirnya pada keberhasilan terapi.

Terbentuknya produk yang toksikChemical degradation may not be

extensive The product of degradation are more

toxic than the original oneContoh:

Tetrasiklin menjadi epianhidrotetrasiklin

Para aminosalisilat menjadi meta aminofenol

Chlorokuin dapat menjadi reaksi toksik, dll.

Stabilitas FisisSifat fisik obat/sediaan obat adalah

sifat yang bisa dilihat dan diuji dengan alat fisis.

Misal: wujud (padat, cair, gas), sistem dispersi (larutan, suspensi,

emulsi), adsorpsi (adsorpsi ke permukaan wadah)

Jika terjadi perubahan fisis, senyawa/entitas kimia obat masih ada, tapi sifat fisisnya berubah.

Contoh perubahan fisis:Pembentukan polimorfi dan hidratHilangnya uniformitas/keseragaman,

misal pada:a. Vaporasi (sublimasi)b. Adsorbsi obatc. Mottling pada tabletd. Creaming pada emulsie. Caking pada suspensi

f. Presipitasi pada larutan, dll.

Stabilitas Fisis

Kriteria menurut USP Chapter <1191>

“The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability, are retained.”

Stabilitas mikrobiologis

Produk obat harus bebas dari kontaminasi mikrobiologis.

Fokus perhatian pada sediaan nonsteril: bioburden total, patogen

Obat-obat tertentu dipersyaratkan steril, spt: sediaan parenteral dan ophthalmic.

Untuk produk obat yang labil thd pertumbuhan mikroorganisme, perlu digunakan preservatif.

Stabilitas Mikrobiologis

Kriteria menurut USP Chapter <1191>“Sterility or resistance to microbial

growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits.”

Stabilitas mikrobiologis

Perlu diperhatikan kualitas bahan baku, sifat peralatan, fasilitas produksi dan operasionalnya (higiene).

Bahan baku yg rentan thd pertumbuhan mikroorganisme adalah bahan yg berasal dari alam (gom, pati, lecithin dll.) perlu monitoring status mikrobiologisnya

1. Solvolisis/hidrolisis

2. Oksidasi3. Fotolisis4. Pirolisis5. Kompleksasi

1. Racemisasi2. Epimerisasi

Rute-rute degradasi obat (kimiawi)

HidrolisisObat yang rentan:Ester-ester (anestetika lokal “kain”,

spt prokain, tetrakain, lidokain; aspirin, alkaloida belladonna.

Amida (penisilin)Imida (barbiturat)Tioester

OksidasiObat yang rentan Katekolamin (senyawa dg gugus –OH terikat pd

atom karbon yg terikat pd cincin aromatik, spt: epinefrin)

Fenol-fenol (phenilephrine, morfin) Senyawa fenotiazin (klorpromazin, prometazin) Senyawa olefin/alkena (senyawa alifatik dg ikatan

rangkap Steroid-steroid Senyawa trisiklik Senyawa tiol (senyawa sulfhidril, spt: captopril) Lain-lain (amfoterisin B, Na nitroprusida,

nitrofurantoin, tetrasiklin, furosemid, ergotamin, sulfasetamid dll)

KompleksasiTetrasiklin dengan ion logam

multivalen (Ca2+, Mg2+, Fe2+, Al2+)EDTAKompleks teofilin dg etilendiamin

membentuk aminofilin adalah kompleks yg dikehendaki utk meningkatkan kelarutan. Permasalahan justru muncul jika teofilin keluar dari kompleks, terutama pd sediaan injeksi.

RasemisasiEpinefrin: enantiomer-l (l-epinefrin) 15-20

kali lebih poten daripada enantiomer-d (d-epinefrin)

Anestetik lokal: mepivacaine, bupivacaine

Faktor-faktor yang mempengaruhi stabilitas produk obat

USP Chapter <1191> “Each ingredient, whether therapeutically

active or pharmaceutically necessary, can affect the stability of drug substances and dosage forms. The primary environmental factors that can reduce stability include exposure to adverse temperatures, light, humidity, oxygen, and carbon dioxide. The major dosage form factors that influence drug stability include particle size (especially in emusions and suspensions), pH, solvent system composition (i.e. percentage of “free” water and overall polarity), compatibility of anions and cations, solution ionic strength, primary container, specific chemical additives, and molecular binding and diffusion of drugs and excipients.”

Ingredient (aktif, eksipien)Lingkungan (suhu, cahaya,

kelembaban, oksigen, dan karbondioksida)

Bentuk sediaan/formula (ukuran partikel, pH, komposisi solven, kompatibilitas anion dan kation, kekuatan ionik, pengemas primer, bahan tambahan kimia ttt, ikatan molekuler obat dan eksipien.

Faktor-faktor yang mempengaruhi stabilitas produk obat

Cara praktis estimasi waktu kadaluwarsa obat

T/10

90(awal)90(baru) Q

TT

T90: waktu kadaluwarsaQ : harga yg didasarkan pada energi aktivasi (Ea) dari persamaan Arrhenius. Harga Q = 3 merupakan harga yang cukup reasonable.∆T : perubahan suhu

ContohSuatu larutan antibiotika mempunyai

waktu kadaluwarsa 96 jam dlm almari pendingin (5oC). Jika larutan tsb harus digunakan dg ambulatory pump pada suhu mendekati suhu badan (30oC) selama 6 jam akankah kadar senyawa bertahan setidaknya 90% dari kadar mula-mula selama durasi pemberian tsb?

Penyelesaian: Langkah 1. Hitung perubahan suhu yg akan

dialami oleh larutan tsb ∆T = 30oC – 5oC = 25oC Langkah 2. Hitung waktu kadaluwarsa pada

temperatur yang baru (dlm ambulatory pump)

Langkah 3. Bandingkan waktu kadaluwarsa yg baru dengan durasi pemakaian

T90 = 6,16 jam; lama pemakaian: 6 jam; maka

jawabannya adalah: ya.

jam 16,63

jam 96

3

jam 96T

5,2/102590(baru)

ContohSebuah resep diterima utk larutan

ophthalmic yg waktu kadaluwarsanya 4 jam pada suhu kamar (25oC). Sediaan obat tsb akan digunakan di ruang dokter pada jam 12.00 keesokan harinya. Dapatkah larutan tersebut disiapkan malam sebelum pemakaian (jam 20.00) dan masih mempertahankan setidaknya 90% kadar zat aktifnya jika disimpan di dalam kulkas (5oC)?

Penyelesaian Langkah 1. Hitung perubahan suhu yg

akan dialami oleh larutan tsb. ∆T = 5oC – 25oC = -20oC Langkah 2. Hitung waktu kadaluwarsa

pada temperatur yang baru

Langkah 3. Bandingkan waktu kadaluwarsa yg baru dg lama simpan di dlm kulkas

T90 = 36 jam; Lama di dlm kulkas = 16 jam; maka jawabannya: ya, bisa.

jam 36 9 . jam 43

jam 4

3

jam 4T

2/102090(baru)

ContohSuatu antibotika hasil rekonstitusi

mempunyai waktu kadaluwarsa pd suhu kamar 3 hari. Berapa lama sediaan itu akan stabil jika disimpan di dalam kulkas (dg estimasi berdasarkan T90)?

Penyelesaian Langkah 1. Hitung perubahan suhunya ∆T = 5oC – 25oC = - 20oC Langkah2. Hitung waktu kadaluwarsa

pada suhu yang baru

hari 27 9 . hari 33

hari 3

3

hari 3T

2/102090(baru)

Sekian dan Terima Kasih

Daftar Pustaka

United States Pharmacopeia Allen Jr. LV (2002), The art, science, and

technology of pharmaceutical compounding, 2nd ed., American Pharmaceutical Association, Washington DC

Thompson JE (1998), A practical guide to contemporary pharmacy practice, 2nd ed., Lippincott Williams & Wilkins

Allen Jr. LV

Homework

Berapa lama beyond-use date sediaan sirup parasetamol yang sudah dikonsumsi bbrp kali tapi belum habis dan disimpan pada suhu kamar?

Records and reportsRecords and reports

1.1. Formulation recordsFormulation records

2.2. Compounding recordsCompounding records

3.3. SOPsSOPs

4.4. Ingredients recordsIngredients records

Thank you..Thank you..