Pharmaceutical Manufacturing Handbook: Production and

356 CONTROLLED-RELEASE DOSAGE FORMS
The degree to which a delivery system can achieve standard release profi les for
a variety of chemically and physically diverse, pharmaceutically active molecules is
a measure of a delivery system ’ s effi cacy and fl exibility (Figure 3 ). Among the most
challenging profi les, linear, zero - order release of highly soluble actives over a 12 –
24 - h period could be considered a reasonable performance standard against which
delivery systems may be judged.
5.1.5.3
Drug level
Maximum desired level
Minimum effective level
Dose Dose Dose Dose
Time
(a)
Maximum desired level
Minimum effective level
FIGURE 3 Profi le of drug level in blood: ( a ) traditional dosing of tablets; ( b ) controlled
drug delivery dose.
Factors Infl uencing Oral Controlled - Release Dosage Forms
Biological Half - Life The usual goal of an oral controlled - release dosage form is
to maintain therapeutic blood levels, as shown in Figure 3 , over an extended period
of time. A drug must be absorbed and enter the circulation at approximately the
same rate at which it is eliminated. The elimination rate is quantitatively described
by the half - life ( t 1/2 ). Each drug has its own characteristic elimination rate, which is
the sum of all elimination process, including metabolism, urinary excretion, and all
other processes that permanently remove drug from the bloodstream.
Therapeutic compounds with short half - lives are excellent candidates for controlled/sustained
- release preparations, since this can reduce dosing frequency [23] .
In general, drugs with half - lives shorter than 2 h, such as furosemide or levodopa,
are poor candidates for controlled - release preparations. Compounds with longer
half - lives, such more than 8 h, also do not need to be in the form of controlled
release, since their effect is already sustained. Digoxin, warfarin and phenytoin are
some examples [24 – 26] . However, drugs having even longer half - lives can be used
in other forms of modifi ed release, such as pulsatile release.
Gastrointestinal Tract and Absorption The design of a controlled - release dosage
form should be based on a comprehensive picture of drug disposition. Both the
pharmacokinetic property and biological response parameter have a useful range
for the design of sustained - and controlled - release products. The potential problems
inherent in oral controlled - release oral dosage forms generally relate to (i) interac-
Drug level
Time
(b)