PH 932

Controlled Release Systems

 Dr. Yuan
Office –HS614.
Hours by appointment.
Xudong.yuan@liu.edu
(718) 4881633

WebCT: Click on course PH 932

 IV route

Cmax
C

steady state

←τ→ Cmin

τ = dosing interval
time
 oral route

Cmax
C steady state

Cmin
← τ →

τ = dosing interval
time
 steady state
“plateau”
[input = output]

Css = ko/KV = ko/Q = 1.44kot1/2/V

time
Under steady state conditions:
Css = ko/KV = ko/Q = 1.44t1/2ko/V
[1/K = t1/2/0.693 = 1.44t1/2 (1.44 = 1/0.693)]
Css is the steady state plasma
concentration of the drug,
ko is the input rate, K is the overall
elimination rate constant (0.693/t1/2),
V is the apparent volume of distribution
and Q is the total body clearance.
Repeat action dosage forms are not, in the
truest sense sustained release dosage forms.
In this case one dose is released immediately,
then a second and perhaps a third
(essentially a series of conventional doses).

Although this produces a “long acting” form

there is some fluctuation between the doses.

The plasma profile looks very much like a

multiple dosing regimen, although,
depending on the relationship between the
half-life of the drug and the interval of the
dose release, steady state may or may not be
achieved.
 Repeat action dosage form

time
A prolonged release dosage
form provides a gradual
release of the drug to
provide a continuous
therapy rather than an
intermittent one.
 Prolonged action dosage form

time
True sustained release forms
combine a conventional or
immediate release form
followed by a gradual release of
the drug. Thus from the initial
time of dosing, the plasma level
does not vary significantly
(from the steady state level).
 Conventional Gradual
(immediate ) release (sustained)
release
C

time
 Advantages of controlled
release dosage forms

•Lack of fluctuation
•Attainment of steady state
•Compliance
•Cost
 Disadvantages of controlled
release dosage forms

•Loss of therapeutic flexibility

•Cost
•Difficult to manufacture
•Hard to titrate drug
F = (AUC)VK/Xo

FA/FB = 0.9 (Bioequivalent)

FA/FB = 0.6 (Not bioequivalent)

 Top ten reasons a drug should NOT be used in a
controlled release dosage form.
1. Very slow absorption
2. Absorption is dissolution controlled
3. Absorption is controlled by physiological factors
4. Very short half-life
5. Very long half-life
6. Very potent
7. Very large dose requires
8. Low therapeutic index
9. Drugs used for acute treatment
10. No relationship between plasma level and
therapeutic activity
 Very slow absorption

time
„Noyes –Whitney Equation:
„

„ dQ/dt = DA(Cs−C)/h

„D is the diffusion coefficient:

D = RT/6Nπηr
 t1/2(a) > t1/2(b)

C a

time
 Dose Dumping
„ These devices usually contain 3 –
4 doses.
„ If the device fails, a large amount
of drug, possibly toxic, can enter
the circulation.
„ This could prove to be dangerous,
even fatal.
„τideal = 1.44t1/2ln(TI)

„If t1/2 = 3 hours and TI = 2,

„τideal = 3 hours
Thus in this case, τ = t1/2,
TI= therapeutic index
 Cmin = Cmax/2
Cmax = 2Cmin
Cmax

C
Cmin

τ = t1/2
time
„ If τ = 2 t1/2

„C min = Cmax/4

„Cmax = 4Cmin
„τideal = (MRT)ln(TI)

„MRT = mean residence time

„MRT = 1/ka + 1/K

 Important Physical-Chemical
Processes and Properties
„ Passive Diffusion
„ Active Transport
„ Dissolution
„ Solubility
• acid/base properties (pKa)
• lipid/aqueous affinity (partition coefficients)
„ Stability
 Fick’s Law
dq/dt = −DA(dC/dx)
dC
Cinitial Cfinal

A
dx
„J = (dq/dt)/A = −D(dC/dx)
„ If dC/dx = − 3 x 10−3 g/cm4 and
„ D = − 6 x 10−7 cm2/sec then
„ J = (− 3 x 10−3 g/cm4)(− 6 x 10−7 cm2/sec)
„ = 1.8 x 10−9 g/sec/cm2

„ ∆G = RT ln(Cfinal/Cinitial)
„ ∆G = RT ln(afinal/ainitial)
„ a = γC
 Site Limited Process

A A
A A
A
A A
nA nA nA
A
1st order A
1st order zero order
A
„−dA/dt = RmaxA
„ Km + A

When A << Km (low concentrations)

−dA/dt = RmaxA / Km (first order)

When A >> Km (high concentrations)

−dA/dt = Rmax (zero order)
 Rmax
zero order
rate

Rmax
2
first order
Km
concentration
 SOME USP DESIGNATIONS for
SOLUBILITY
Designation ml solvent/gram solute
Very soluble less than 1
Freely soluble 1 to 10
Soluble 10 to 30
Sparingly soluble 30 to 100
Slightly soluble 100 to 1000
Very slightly soluble 1000 to 10,000