The document discusses factors that influence drug dissolution and absorption from drug products, including physicochemical properties of drugs and excipients used in formulations. It describes how properties like partition coefficient, pH stability, solubility, particle size, and polymorphic form can impact a drug's release and bioavailability. Common excipients used in solid and liquid dosage forms are also outlined, and how they can affect drug performance.
3. Pendahuluan
Biofarmasetika : ilmu yang mempelajari hubungan sifat
fisikokimia-formulasi obat terhadap bioavailabilitas obat (in
vtro- in vivo) dan sistem penghantaran obat dalam tubuh
pada kondisi normal maupun kondisi patologis.
4.
5. Biopharmaceutis : (Woolf, 1981)
• Pharmaceutics : preparations, use, or dispensing medicines
• Bio : relating to living organism or tissues
Sciences of preparing, using
and administering drugs to
living organism or tissues
ADME
6. BIOFARMASI
ILMU YANG MEMPELAJARI HUBUNGAN ANTARA :
(1) SIFAT FISIKO-KIMIA ZAT AKTIF,
(2) FAKTOR FORMULASI SEDIAAN OBAT (DOSAGE FORM) DAN
(3) FAKTOR TEKNOLOGI PEMBUATAN SEDIAAN OBAT,
DENGAN
BERBAGAI PROSES YANG DIALAMI OBAT DALAM TUBUH SAMPAI
ZAT AKTIF MASUK KE DALAM SISTEM PEREDARAN DARAH:
LIBERASI, DISOLUSI, DIFUSI, TRANSFER, ABSORPSI.
7. APLIKASI
•kinerja (performance)
efektif, cepat bekerja
Menghindar/meminimalkan
terjadinya efek samping
bekerja dalam jangka waktu
yang diinginkan
dosis efisien
mendapatkan
sediaan obat
(drug dosage
form) yang
memiliki :
8. • Perjalanan obat dalam tubuh dapat dibagi dalam fase:
• Tahapan Biofarmasetik:
i. Liberasi (Pelepasan)
ii. Disolusi (Pelarutan)
iii. Absorpsi
• Tahapan Farmakokinetika:
ADME
Obat Fase
Biofarmasetik
Fase
Farmakokinetik
Fase
Farmakodinamik
10. Rute pemberian Obat
• Tiap rute pemberian obat harus memperhatikan pertimbangan
biofarmasetik dalam rancangan produk sediaan.
• Mis: formulasi sediaan mata harus mempertimbangkan pH,
isotonisitas, sterilitas dan iritasi lokal.
• Rute pemberian obat terdiri atas:
Ekstravaskular
Intravaskular
11. Sifat fisiko-kimia zat aktif:
Kelarutan, ukuran partikel, bentuk
kristal, sifat asam/basa, dll
12. Faktor formulasi:
Jenis dan jumlah eksipien yang digunakan
(bahan penghancur tablet, pengikat tablet,
pengisi tablet, basis supositoria, dll.)
14. • Faktor formulasi yang mempengaruhi kecepatan melarutnya zat aktif salah
satunya adalah penambahan eksipien.
• Penambahan eksipien bertujuan untuk:
menghasilkan sifat dan bentuk tertentu obat dan bentuk sediaannya.
untuk meningkatkan kompresibilitas bahan aktif, meningkatkan
kestabilan bahan aktif, mengontrol laju absorpsi, serta meningkatkan
bioavailabilitas obat.
15. • Absorpsi (Penyerapan)
Absorpsi adl masuknya molekul obat dari tempat pemberian ke jalur
sistemik setelah melewati membran biologis.
Absorpsi hanya terjadi terhadap molekul obat dalam keadaan terlarut.
Kecepatan absorpsi ditentukan oleh tahap Pelepasan dan Pelarutan.
Tahap yang paling lambat menjadi tahap penentu kecepatan absorpsi = Rate
limiting step.
17. PROSES BIOFARMASETIK YANG
DIALAMI OBAT DALAM TUBUH
Pelepasan
(liberation)
Pelarutan
(dissolution)
Transfer
Difusi
(diffusion)
Absorpsi
(absorption)
18. I. Proses Pelepasan (Liberation)
Mekanisme Yang Terjadi Tergantung Keadaan Zat
Aktif Dalam Sediaan:
Zat Aktif Tercampur Secara Fisik (Bentuk
Sediaan Padat: Tablet)
Zat Aktif Terlarut Dalam Pembawa (Supositoria,
Salep)
Zat Aktif Terdispersi (Suspensi, Emulsi)
19. I. PROSES PELEPASAN (LIBERATION)
MEKANISME YANG TERJADI TERGANTUNG
KEADAAN ZAT AKTIF DALAM SEDIAAN:
ZAT AKTIF TERCAMPUR SECARAFISIK
(BENTUK SEDIAAN PADAT: TABLET)
ZAT AKTIF TERLARUT DALAM PEMBAW
A
(SUPOSITORIA, SALEP)
ZAT AKTIF TERDISPERSI (SUSPENSI,
EMULSI)
20. ► Mekanisme proses pelepasan yang
terjadi berbeda-beda untuk tiap
bentuk sediaan
► Lepasnya zat aktif dari pembawa bisa dalam
keadaan/bentuk partikel yang belum terlarut
(dari tablet), bisa sebagai bentuk molekul
(dari supositoria basis lemak dimana zat aktif
terlarut dalam basis)
21. Pelepasan dari sediaan TABLET
TABLET INTI (TIDAK BERSALUT)
DISINTEGRATION I
POWDER (DRUG AND EXIPIENT)
GRANUL
DISINTEGRATION II (LIBERATION)
TABLET SALUT
PELARUTAN PENYALUT
23. BAHAN PENGHANCUR TABLET YANG MENGEMBANG :
PATI/AMILUM (SINGKONG, BERAS, DLL.)
PATI YANG DIMODIFIKASI (PRE- GELATINIZED)
AC-DISOL
DLL.
BAHAN PENGHANCUR KARENA REAKSI
KIMIA:
NATRIUM BIKARBONAT
24. Mekanisme hancurnya supositoria
MELELEH PADA SUHU TUBUH (PEMBAWA
LEMAK, SEPERTI OL. CACAO)
MELARUT DALAM CAIRAN REKTAL (SEPERTI BASIS
PEG)
25. Pelepasan dari supositoria
Hancurnya Pembawa (Meleleh Atau Melarut)
Partisi Dari Pembawa Ke Cairan Rektal Diikuti Proses
Difusi Dalam Pembawa (Jika Terlarut Dalam
Pembawa Untuk Kasus Pembawa Supositoria Basis
Lemak Seperti Oleum Cacao) Dan Dalam Cairan
Rektal Dari Konsentrasi Tinggi Ke Konsentrasi
Rendah
26. Pelepasan dari
sistem dispersi
emulsi
(zat aktif
terlarut dalam
fase internal)
• TERJADI PERPINDAHAN ZAT AKTIF DARI FASE EKSTERNAL KE CAIRAN
TUBUH TEMPAT PEMBERIAN OBAT BERDASARKAN PERBEDAAN
KONSENTRASIDAN KOEFISIENPARTISI.
• TERJADINYA PERPINDAHAN ZAT AKTIF KE MEDIUM LAIN DIIKUTI
PROSESPERPINDAHAN/DIFUSI MOLEKUL ZAT AKTIF DALAM
MEDIUMPEMBAWADARIKADARTINGGIKEKADARRENDAH.
27. Pelepasan dari sistem dispersi suspensi
PERPINDAHAN ZAT AKTIF DARI SUATU MEDIUM PEMBAWA
OBAT/SEDIAAN YANG JENUH DENGAN ZAT AKTIF KE MEDIUM LAIN
(CAIRAN TUBUH PADA TEMPAT PEMBERIAN OBAT) BERDASARKAN
PERBEDAAN KONSENTRASI DAN KOEFISIEN PARTISI.
PERPINDAHAN TERJADI PADAANTAR-PERMUKAAN.
TERJADINYA PERPINDAHAN KE MEDIUM LAIN DIIKUTI PROSES
PELARUTAN ZAT AKTIF DAN PROSES DIFUSI DALAM MEDIUM
PEMBAWA.
28. II. PROSES PELARUTAN/DISOLUSI
PROSES PELARUTAN/DISOLUSI TERJADI JIKA ZAT AKTIF DALAM KEADAAN
TIDAK TERLARUT DALAM SEDIAAN (MISALNYA DISPERSI DALAM PEMBAWA
MINYAK).
PROSES PELARUTAN TERJADI DALAM PEMBAWA SEDIAAN ATAU SETELAH
LEPAS DARI SEDIAAN (MISALNYA DARI SEDIAAN TABLET.
29. III. PROSES DIFUSI
TERJADI DALAM SUATU MEDIUM
DALAM KEADAAN ZAT AKTIF
TERLARUT DALAM MEDIUM.
MOLEKUL ZAT AKTIF BERGERAK DARI
KADAR TINGGI KE KADAR RENDAH.
33. Physicochemical Properties for Consideration in
Product Design
Partition
Coefficien
t
Give some indication of the relative affinity of the
drug for oil & water. Adrug that has high affinity for
oil may have poor release & dissolution
Excipient
Interactio
n
Compatibility of the excipients with the drug
Sometime trace elements in excipients may affect the
stability of the product. Specification is important
pH Stability
Profile
Stability of solutions is often affected by the pH of
vehicle. pH in the stomach & gut is different, know-
ledge of stability would help to avoid degradation
34. Solubility, pH, & Absorption
▶pH environment of the GIT varies from acidic in the
stomach to slightly alkaline in the small intestine
▶Abasic drug is more soluble in an acidic medium
▶Solubility may be improved with the addition of an
acidic or basic excipient
▶Buffering agent may be added to slow or modify the
release rate of a fast dissolving drug
▶Controlled release drug product must be a non
disintegrating dosage form.
35. Stability, pH, & Absorption
• If drug decomposition occurs by acid or based
catalysis, some prediction for degradation of the
drug in GIT may be made
• Erythromycin decomposition occurs rapidly In
acidic medium. It has to be enteric coated to protect
against acid degradation in the stomach
36. Particle Size & Absorption
• Surface area of the drug is increase enormously by
a reduction in the particle size. The greater the
surface area the more rapid the rate of diss
• Particle size & distribution studies are important
for drug that have low water solubility. Many
hydrophobic drugs are very active IV-ly but are not
very effective orally due to poor absorption.
37. Particle Size & Absorption
• Griseofulvin, nitrofurantoin & many steroids are drug
with low aqueous solubility; micronized form has
improved absorption.
• Smaller particle size results in an increase in the
surface area, enhances water penetration, an increases
the dissolution rates.
• Adisintegrant may be added to the formulation to
ensure rapid disintegration
• Surface-active may increase wetting & solubility
38. Polymorphic Crystals, Solvates, & Absorption
• Polymorphism (drug in various crystal forms). Same
chemical structure but different physical properties
• Crystals have lower solubility than the amorphous
• Chloramphenicol, has several crystal forms, when given
as a suspension, the conc is dependent on % of β-
polymorph. β-form is more soluble & better absorbed
• Crystal form has the lowest free energy is the most
stable. A drug that exists as an amorphous form,
dissolves more rapidly than rigid crystalline form
39. Polymorphic Crystals, Solvates, & Absorption
▶Some polymorphs are metastable, a change in
crystal form may cause problems in
manufacturing. Achange in the crystal structure
may cause cracking in a tablet.
▶Some drugs interact with solvent to form a
crystal called solvate.
▶Water may form a special crystal called hydrates.
Erythromycin hydrates have different solubility
compared to the anhydrous form.
▶Ampicillin 3H2O was reported to be less
absorbed than the anhydrous forms.
40. FAKTOR FORMULASI YG
MEMPENGARUHI DISOLUSI
Penambahan eksipien
• Untuk menghasilkan sifat dan bentuk tertentu
obat dan bentuk sediaannya
• Untuk meningkatkan kompresibilitas bahan aktif,
kestabilan thd penguraian, mengurangi iritasi GIT,
kontrol laju absorbsi, meningkatkan bioavalabilitas
obat
44. Excipients Used in Oral Liquid
Alcohol Solubilizing agent, preservative
PEG Solubilizing agent
Methyl, propyl-paraben Preservative
Sucrose Sweetener
Sucrose Sweetener
Polysorbates Surfactant
Sesame oil, Corn oil For emulsion vehicle
45. Excipient may affect dissolution
▶Mg stearate, may repel H2O & reduce dissolution
when used in large quantities. Coatings, particularly
shellac upon aging can decrease the dissolution rate.
▶Low concentration of surfactants decrease the
surface tension & increase the rate of drug
dissolution. Higher surfactans concentration tend to
form micelles with the drug & decrease the
dissolution rate.
▶Large drug particles have a smaller surface area
dissolve more slowly than smaller particles.
▶High compression of tablets without sufficient
disintegrant may cause poor disintegration.
46. Excipient may affect dissolution
▶NaHCO3 may change the pH of the medium. Aspirin, a weak acid when
formulated with NaHCO3 will form a water-soluble salt, in which the drug
rapidly dissolves.
▶Excipients in a formulation may interact directly with the drug to form a water
soluble/insoluble complex.
▶If tetracycline is formulated with CaCO3, an insoluble complex of Ca tetracycline
is formed that has a slow rate of dissolution & poor absorption.
47. Excipi
ents
▶That increase the solubility of the drug increase the rate of
dissolution & absorption
▶May increase retention time drug in GIT & increase absorption
▶May act as carries to increase drug diffusion across the
intestinal wall. Many excipients may retard dissolution &
absorption.
▶Various excipients that are pharmacodynamically inert but that
functionally enhance the drug & the dosage form
▶Tablets: diluent (lactose); disintegrant (starch); lubricant (Mg
stearate ); binding & stabilizing agents. Improperly used: the
rate & extent of absorption may be affected.
▶Increasing the amount of disintegrant may overcome the
retarding effect of lubricant on dissolution. Some poorly
soluble drugs increase in disintegrant level has little effect on
dissolution because the fine drug particles are not wetted
48. References
▶Shargel, L. & Yu,A. (2016). Applied Biopharmaceutics &
Pharmacokinetics. 4th Ed. New York: Appleton & Lange.
▶Paradkar, A.R. & Bakliwal, S.R. (2008). Biopharmaceutics &
Pharmacokinetics.
▶Wagner, J.G. (2008). Biopharmaceutics and Relevant
Pharmacokinetics. Drug Intelligen Publications.
▶Related articles in several journals