5
4
3
2
1
0 4 8 12
Benzocaine, mg
16 20 24 28
Time, min (A)
0 2 4 6 8
1 2 3 4 5 6
% Polysorbate 80 (B) 102 Cs gm/mL
to influence the dissolution rate of many drugs from solid dos-age forms. Environmental conditions to which dosdos-age forms are exposed, moisture in particular, should be rigorously assessed, if reproducible and reliable dissolution data are to be obtained.
Additionally, humidity during the manufacture of the dosage forms should be carefully controlled to reproduce the quality of the product from batch to batch.
Detection errors
Two most common variables leading to inter-laboratory dis-agreement are the failure to use standards during analysis and external vibration.25 Extreme care must be exercised when lab-oratory methods are introduced into quality control to ensure that no part of the equipment interferes with sensitive deter-minations.
Despite the fundamental relationship between bioavailabil-ity and dissolution rate, the present evidence suggests that no single dissolution-rate test can be applied to all drugs. The pos-sibility that a single test may be applied to drugs having similar physicochemical properties remains to be established. These observations are attributable, primarily, to the inability to assess and control the many variables affecting the dissolution process of a drug substance.
sources of Variability compendial methods
When selecting apparatus for dissolution testing, routine quality control, new drug development, or complying with regulatory
requirements, the analyst must follow the latest issue of com-pendia, including revisions. The modifications introduced in the dissolution testing methods, during recent years, are so numerous that even revisions two or three years old may be outdated.
USP/NF Method 1 (Rotating Basket Method)The USP/NF rotating basket method of dissolution testing essentially con-sists of a 25.0 ± 3.0mm diameter × 37.0 ± 3.0mm high stainless-steel 40-mesh wire basket, rotated at a constant speed ranging from 25 to 150 rpm. It is immersed in 900 ml of dissolution medium in a vessel of 1000 ml capacity. The medium in the vessel is maintained at a constant temperature of 37 ± 0.5°C by means of a suitable water bath. The environment in which the apparatus is placed should not contribute significant motion, agitation, or vibration to the assembly. A fitted cover may be used to retard evaporation. The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly without any significant wobble (Fig. 6-18).
The dosage unit is placed in a dry basket at the beginning of each test. Distance between inside bottom of the vessel and the basket is maintained at 25 ± 2 mm during the test.
In case of non-disintegrating dosage forms, this apparatus is superior to Apparatus 2, since it constrains the dosage form in steady state fluid flow. This method may seem inferior for
figure 6-17. Effect of viscosity on dissolution rate.18 A. Relation-ship of total solubility (Cs) of benzoic acid at 25° to dissolution rate and concentration of polysorbate 80. •, rate;, • concentration. B.
Relationship of viscosity to dissolution rate of benzoic acid in aque-ous methylcellulose solutions at 25°.
120 140 160 180 200
5
5 10 15 20
10 15 20 25 30
Dissolution rate× 10
4 ,2mg/cm/sec POLYSORBATE 80, %
Cs,mg/mL (A)
20
20 40 60 80 100 120 140 160
40 60 80 100 120
Dissolution rate × 10
4 ,2 mg/cm/sec
ηrel
(B)
6.3 to 6.5 or 9.4 to 10.1 mm
Vent hole 2.0 ± 0.5 mm diameter
A Retention spring with 3 tangs on 120° centers
Clear opening 20.2 ± 0.1 mm
37.0 ± 3.0 mm
27.0
± 1.0 mm open screen
NOTE—Maximum allowable runout at “A” is ± 1.0 mm when the part is rotated on CL axis with basket mounted.
20.0 ± 1.0 mm 25.0 ± 3.0 mm
5.1 ± 0.5 mm
Screen O.D.
22.2 ± 1.0 mm
Screen with welded seam;
40 × 40 mesh, 0.25-mm wire diameter with wire openings of 0.40 ± 0.04 mm; where 20-mesh screen is specified, use 20 × 20 mesh, 0.40-mm wire diameter with wire openings of 0.90 ± 0.09 mm. [Note—
After welding, the screen may be slightly altered.]
figure 6-18. USP Apparatus 1.
testing of dosage forms, which contain gums, due to the clog-ging of screen matrix. In case of floating dosage forms, this method performs well, but care should be taken that excipients do not clog the basket mesh.
USP/NF Method 2 (Rotating Paddle Method)—For all prac-tical purposes, the compendial specifications outlined for this method are identical to method 1, except that the paddle is substituted for the rotating basket.
The metallic or suitably inert, rigid blade and shaft comprise a single entity. The paddle and blade shaft may be coated with suitable inert coating. The dosage form is allowed to sink to the bottom of the vessel before rotation of the blade is started. This apparatus is frequently used for both disintegrating and non-disintegrating dosage form at 50 rpm. Other agitation speeds are acceptable with proper justification.
USP/NF permits variation in the paddle method involving the use of a helix of non-reactive material as a “sinker” for floating dosage forms. Anchoring accomplished by such a device has been severely studied (Fig. 6-19).
In cases of basket and paddle methods, “cone formation”
problem has been reported in cases of some of the products.
A dosage form containing high amounts of insoluble excipients is expected to form a dense mass at the bottom of the vessel.
This cone formation was observed for both poorly and highly soluble drugs, but it has more impact on poorly soluble drugs.
The cone formation is less pronounced in cases of basket method, because the dosage is placed in the basket, instead of being dropped at the bottom of vessel, as in paddle method.
To eliminate this problem mostly seen in paddle method and,
hence, to improve the reproducibility of the dissolution test, several modifications to the paddle method were suggested and investigated. They are the tilted vessel, the Peak™ vessel with a cone-shape molded into the bottom of the vessel, metal strip, crescent-shaped spindles, mega-paddle, and various propeller shapes. There was discussion regarding use of the peak vessel, because it is not standard equipment. Peak vessel use requires documented justification. It was pointed out that increasing paddle speed often eliminates the cone, but there are limits as to how high the paddle speed can go without losing discrimi-natory power. Although a comment was made that reducing the amount of excipients in the formulation could reduce or eliminate the cone, it was pointed out that cone formation and dissolution should not be the driving force to modify a formula-tion. A flow-through cell apparatus was suggested, as an alterna-tive to minimize cone formation.
USP/ NF Method 3 (Reciprocating Cylinder)—The assembly consists of a set of cylindrical, flat bottomed glass vessels; a set of glass reciprocating cylinders; stainless steel fittings (type 316 or equivalent) and screens that are made of suitable non-sorbing material and non-reactive material designed to fit the top and bottoms of the reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels and, if desired, index the reciprocating cylinders hori-zontally to a different row of vessels. The vessels are immersed in suitable water bath of any size that permits holding the temperature at 37 ± 0.5°C during the test. The components conform to the specifications, as shown in Figure 6-20, unless otherwise specified in the individual monograph.
One advantage of reciprocating cylinder is that gastroin-testinal tract conditions can be easily simulated, as it is easy to make time dependent pH changes. This apparatus is most suitable for non-disintegrating (extended release) or delayed-release (enteric coated) dosage forms.
USP Apparatus 4 (Flow-Through Cell)—The assembly consists of a reservoir and a pump for dissolution medium;
a flow-through cell; and a water bath that maintains dissolu-tion medium at 37 ± 0.5°C. The pump forces the dissolution medium upwards through the flow-through cell. The pump has a delivery range between 240 and 960 ml/ hr, with the stan-dard flow rates of 4, 8, and 16 ml/min. It must be volumetric to deliver constant flow independent of flow resistance in the filter device; the flow profile is sinusoidal with a pulsation of 120 ± 10 pulses/min.
The components conform to the specifications, as shown in the Figure 6-21, unless otherwise specified in the monograph.
The advantages of flow through cell apparatus most often cited are the ability to test drugs of very low aqueous solubility in the open loop mode and the ability to change the pH con-veniently during the test. The disadvantage associated with it might be the operational difficulties of preparing large volumes of medium for operation in the open loop mode and the added time in the system set up and cleaning.
USP Apparatus 5 (Paddle Over Disk)—The Apparatus 2 is used with the addition of a stainless steel disk assembly, designed for holding the transdermal system at the bottom of the vessel. Temperature is maintained at 32 ± 0.5°C. A distance of 25 ± 2 mm between the paddle and blade and the surface of the disk assembly is maintained during the test. The ves-sel may be covered during the test to minimize evaporation.
Disk assembly for holding the transdermal system is designed to minimize any “dead” volume between the disk assembly and the bottom of the vessel. Disk assembly holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade. (For more specifications, refer to Fig. 6-22.)
USP Apparatus 6 (Rotating Cylinder)—The vessel assembly used is the same as Apparatus 1, except the basket and the shaft is replaced with a stain-less steel cylinder stirring element to maintain the temperature at 32 ± 0.5°C during the test. The shaft and cylinder components of the stirring element are fabri-figure 6-19. USP Apparatus 2.
9.4 to 10.1 mm diameter before coating
NOTES —
(1) Shaft and blade material 303 (or equivalent) stainless steel.
(2) A and B dimensions are not to vary more than 0.5 mm when part is rotated on CL axis.
(3) Tolerances are ± 1.0 mm, unless otherwise stated.
41.5 mm radius 1.2 mm radius
B
42.0 mm
74.0 mm to 75.0 mm
40 ± 10 mm 19.0 mm
± 0.5 mm 35.8 mm A
figure 6-20. USP apparatus 3. (All measurements are expressed in mm unless noted otherwise.)
50.8 ± 1
Air holes
3.9 ± 0.1 diameter
Evaporation cap
66.8 ± 1
38.1 ± 1 6–8 diameter
Type 316 stainless steel Air holes
3.9 ± 0.1 diameter Mesh screen
Glass reciprocating cylinder
Mesh screen
47 ± 1.4
Glass vessel
180 ± 1
18 ± 1 100 ± 1 Inner tube length23 ± 1
23–26
cated of stainless steel to the specifications, as shown in Figure 6-23. The dosage units are placed on the cylinder at the begin-ning of each test. The distance between the inside of the vessel and the cylinder is maintained at 25 ± 2 mm during the test.
USP Apparatus 7 (Reciprocating Cylinder)—The assembly consists of a set of volumetrically calibrated or tared solution containers made of glass or other suitable inert material; a motor and drive assembly to reciprocate the system vertically and to index the system horizontally to a different row of ves-sels automatically, if desired; and a set of suitable sample hold-ers. (For details on specifications, refer to the Fig. 6-24.)
Dissolution of immeDiate release soliD oral Dosage forms
In vitro dissolution tests for immediate release solid oral dos-age forms, such as tablets and capsules, are used to (1) assess the lot-to-lot quality of a drug product; (2) guide development
of new formulations; and (3) ensure continuing product quality and performance.
For the drug approval process, it is essential to have the cur-rent knowledge about solubility, permeability, dissolution, and pharmacokinetics of a drug product. Based on drug solubility and permeability, the following Biopharmaceutical Classifica-tion System (BCS) is recommended in the literature:27
Class 1: High solubility-High permeability drugs Class 2: Low solubility-High permeability drugs Class 3: High solubility-Low permeability drugs Class 4: Low solubility-Low permeability drugs
This classification can be used as a basis for setting in vitro dissolution specifications and in vivo/in vitro correlation (IVIVC). The BCS suggests that, for high solubility, high perme-ability (Class 1) drugs and, in some cases for high solubility, low permeability (Class 3) drugs, 85% dissolution in 0.1N HCl in 15 minutes can ensure that bioavailability is not limited by dissolution. In case of low solubility, high permeability drugs (Class 2), drug dissolution may be the rate-limiting step for drug absorption, and an IVIVC may be expected. A dissolution profile in multiple media is recommended for drug products in this cat-egory. In case of high solubility, low permeability drugs (Class 3), permeability is the rate controlling step, and a limited IVIVC may be possible, depending on the relative rates of dissolution and intestinal transit. Drugs in low solubility, low permeability (Class 4) present significant problems for oral drug delivery.
The regulatory acceptance of in vitro (dissolution) testing as a reliable surrogate for an in vivo bioavailability study is com-monly referred to as “biowaiver.” Biowaiver may be granted for BCS Class 1 (high solubility, high permeability) drug products for bioequivalence studies, if the drug product is rapidly dis-solving. The drug product is considered rapidly dissolving, if not less than 85% of the labeled amount of the drug substance dissolves within 30 minutes, using US Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.28
Dissolution of poWDers
There is no official method in the USP for dissolution testing of powders. The only application of powder dissolution in the USP is the evaluation of the intrinsic dissolution of powders in gen-eral chapter <1087> of the USP 34. However, in this method, the powder is pressed into a tablet, like a disk with a defined surface. The dissolution from the surface is evaluated. Dissolu-tion testing of finely divided particles can be performed using paddle method or flow-through cell method.
Dosage forms for oral caVity
Dosage forms for the oral cavity, such as sublingual tablets, buccal tablets, chewing gums, and chewable tablets, are solid dosage forms placed in the mouth, allowing the active ingredient to dissolve in the saliva and then absorb either via the oral route or by the buccal/sublingual mucosa within the mouth.29,30
• Chewable tablets: USP has stated the need to use paddle method for chewable tablets, with the exception of ampicillin chewable tablets where basket method is sug-gested, and for carbamazepine chewable tablets, where both USP apparatus 2 and 3 are suggested. There have been suggestions to use USP apparatus 3, a reciprocating cylinder, along with glass beads, to create a large amount of agitation within the dissolution medium.
• Buccal/Sublingual tablets: In general, the drug release studies from buccal/sublingual tablets has been carried out using USP apparatus 2 (paddle). Modified Franz diffu-sion cell also has been suggested for these dosage forms.
• Chewing Gums: The USP has not yet created an apparatus
Dissolution vessel
Paddle
Disk assembly Disk assembly
A
A 3.0
41.2
25 ± 2
figure 6-22. USP apparatus 5 (Paddle over disk). (All measurements are expressed in mm unless noted otherwise.)
to test the release of medication from chewing gums. How-ever, the European Pharmacopoeia provides a description of a stainless steel 3-piston-apparatus that is required for testing of “medicated chewing gums.” The test is typically operated at 37°C and at 60 cycles/min. Test media with a pH of 6 are commonly used, since this pH corresponds to reported saliva pH values of 6.4 (adults) or 7.3 (children).
However, to date, there has been insufficient international experience with this apparatus to draw a firm conclusion about its suitability.
Dissolution of orally Disintegrating tablets31
Orally disintegrating tablets (ODT) are solid dosage forms that disintegrate in the oral cavity, leaving an easy to swallow resi-due. ODT have high porosity, low density, and low hardness.
The time for disintegration for ODT is considered less than 1 min. Development of dissolution methods for ODT is compa-rable to the approach taken for conventional tablets, except when the tablets utilize taste masking. Media that can be used are 0.1 N hydrochloric acid, pH 4.5 and 6.8 buffers. The most commonly used apparatus for running dissolution test for ODT is USP Apparatus 2 (paddle method) with a paddle speed of 50 rpm. USP Apparatus 1 is less frequently used, due to the physical properties of these tablets, as the tablet fragments or disintegrated tablet masses may become trapped in the basket, yielding poorly reproducible dissolution profiles. Since dis-solution for ODT is very fast, slower speeds are employed. In figure 6-21. USP apparatus . A. Large cell for tablets and capsules. All measurements are expressed in mm unless noted otherwise. B. Tablet holder for the large cell All measurements are expressed in mm unless noted otherwise. C. Small cell for tablets and capsules. All measurements are expressed in mm unless noted otherwise. D. Tablet holder for small cell. All measurements are expressed in mm unless noted otherwise.
Filter chamber Sieve 40 mesh
d = 0.2 w = 0.45 d = 0.2 w = 0.45
Score for the tablet holder
Score for the tablet holder
A
B D
C min 3
Ø = diameter Ø0.8 ± 0.05
2.5 ± 0.25 2.5 ± 0.25
Ø0.8 ± 0.05 Ø12 ± 0.2
Ø20 ± 0.2
155
35.5 ± 0.5 Ø20 ± 0.2
Ø22.6 ± 0.2
40° ± 1°
(Ø3)
(Ø3)
50 ± 0.5 15 5.5 ± 0.5
min. 3
Filter chamber Sieve 40 mesh
40° ± 1°
50° ± 1°
0.5 0.5
+0.5
6.5 6.5
7.5
9.5
R3
24.00+0.5 13.5
6
0 9.5
4.45 ± 0.02 Four holes at 1.111 ± 0.02
dis. equally spaced on 2.54±
0.02 dis. b.c at 63.4° ± 0.5°
angle to surface.
0.94−1.01 dis.
63.4° ± 0.5°
figure 6-23. USP apparatus 6. (All measurements are expressed in cm unless otherwise noted.)
Parker O-ring
1.98 O Plate use O-ring 2-225-V884-75 OR
1.42 O Plate use O-ring 2-218-V884-75
Virgin Teflon O = diameter
Stainless Steel Tubing 12" × 3/16 O
figure 6-24. USP apparatus 7.
the case of tablets exceeding 1 gram and containing relatively denser particles, larger mounds may be produced on dissolu-tion, which may be prevented by using higher paddle speeds.
These two situations expand the suitable range to 25–75 rpm.
Dissolution of topical Dosage forms32
Drug-release studies from gels, creams, and ointments are becoming an important step, both during the developmental stages of new formulations and as a routine quality control test for assuring the uniformity of the finished product. Also, these studies can often provide useful information on some physi-cochemical parameters involved in the in vivo percutaneous absorption, such as the diffusion coefficient and the solubility of the drug in the specific vehicle used.
Although many investigators have conducted drug release-rate studies from topical dosage forms, it appears that no single appa-ratus or procedure has emerged as the most favored or accepted as a quasi-standard for others in the field. According to FDA guidelines, the most commonly used method is as follows:
In vitro dissolution method for topical dosage forms is based on an open chamber diffusion cell system, such as a Franz cell system, fitted usually with a synthetic membrane. The test product is placed on the upper side of the membrane, in the open donor chamber of the diffusion cell, and a sampling fluid is placed on the other side of the membrane, in a receptor cell.
Diffusion of drug from the topical product to and across the membrane is monitored by assay of sequentially collected sam-ples of the receptor fluid.
Aliquots removed from the receptor phase can be analyzed for drug content by high-pressure liquid chromatography (HPLC) or other analytical methodology.
Dissolution of suspensions
Although most dissolution studies during the last two decades have concentrated on tablets and capsules, some studies have pointed to the importance of the dissolution characteristics of drugs administered in suspension. This is hardly surprising, as suspensions are similar to the disintegrated form of tablets and capsules; if dissolution has become a priority for these formula-tions, it is logical to extend its concept to suspensions. Indeed, several studies show that the absorption of several poorly solu-ble drugs administered in suspension formulations are dissolu-tion rate-limited.
Such in vivo/in vitro correlation studies have confirmed the importance and the viability of dissolution rate deter-minations of suspensions, as a discriminative test for rapid screening of new formulations and to control lot-to-lot
Such in vivo/in vitro correlation studies have confirmed the importance and the viability of dissolution rate deter-minations of suspensions, as a discriminative test for rapid screening of new formulations and to control lot-to-lot