Tablets, capsules, the "pink medicine" that sits onrefrigerator shelves to help nurse small children with sore throats and earinfections—and now more exotic formulations such as transdermal patches andmedicated stents—all must be rigorously tested to ensure that they actuallydeliver the active pharmaceutical ingredient as promised. And delivery is muchless a sure thing than it was in the past, says Greg Martin, president ofComplectors Consulting and a widely acknowledged expert in the field.
For more than 30 years, Martin has applied his knowledge andexperience to solving the ongoing riddles that frequently bedevil drugdelivery. He points out that the dissolution method is important because it isthe only in-vitro test that addressesproduct availability. It is a primary quality control test that all productsmust pass to be on the market. With evolving dosage forms, the dissolution test(or what might be called the in-vitrorelease test) is constantly being improved or changed with newer equipment andmethods.
In terms of solubility, "we've harvested most of thelow-hanging fruit," Martin says.
In most categories, effective drugs already exist. Todevelop new drugs to replace them, researchers search out exotic molecules thatare almost always less soluble. Poor solubility may account for 60 to 90percent of the small molecules for oral administration now in development, withsolubility off an order of magnitude or more.
"Buffered media doesn't work at all, or works poorly,"Martin says, and this leads dissolution chemists to use aqueous surfactantsolutions such as sodium lauryl sulfate or a commercial product called Tween80. Some drug developers are experimenting with ligands such aspolysaccharides, while others are exploring the use of surfactants as part ofthe drug formulation, all aimed at dealing with poor inherent solubility.
Setting appropriate specifications for the test is achallenge for the industry and the regulatory agencies. Harmonization of thedissolution test is an ongoing point of discussion, as is the calibration ofthe equipment. The goal of relating the in-vitrotest to in-vivo drug pharmacokineticdata is still a centerpiece for many discussions concerning the ability of thetest to predict bioequivalence.
Method design
Traditionally, dissolution methods have been developed asquality control tests, Martin notes. More recently, biorelevant dissolution hasbeen useful as a formulation selection tool during drug product development.Dissolution tests may be developed in pursuit of an in vivo/in vitro correlation (IVIVC) to justify scale-up orpost-approval changes or to obtain biowaivers when introducing a lower potency,he observes. Hence, it is important to identify the purpose before developing adissolution method.
"What type of dosage form will be tested? Test conditionsfor an immediate release product will be different from those for an extendedrelease or delayed release product, and the apparatus used for a tablet mightbe different from one used for a transdermal patch or medicated stent," Martinsays.
Test apparatus
Martin notes that two types of test apparatus dominate thetechnology: U.S. Pharmacopeial Convention (USP) Apparatus 1 and 2—with 2, whichinvolves dropping the dosage form into a dissolution vessel and stirring themedium with a paddle, being the most popular. Apparatus 1 uses a mesh basketthat contains the dosage form in place of the paddle. In both cases, samplesare withdrawn from the vessel at regular periods using UV-visible spectroscopyor HPLC. Fiber-optic probes, resident insitu in the vessel, send the signal directly to the spectrometer.
A distant third inpopularity—at least in the United States—is Apparatus 4, in which a constantflow of the solvent media moves across the dosage form. SOTAX, a Swiss company,now provides what it describes as a fourth-generation, flow-through cell systemthat has been designed to overcome potential challenges linked to methoddevelopment for a variety of dosage forms.
Stents are one such challenge, sincethey are designed to release products over a period of months. With theflow-through cell, fresh media passes continuously across the dosage form in anopen loop system. A semi-automated system allows samples to be takensimultaneously and collected in a fraction collector or analyzed directly by UV.Dissolution can also be analyzed in situin a fiber-optic dissolution system.
Tests using both Apparatus 1 and 2 have been the subject ofan abiding controversy occasioned by the American Society for Testing andMaterials (ASTM) stepping in, at the U.S. Food and Drug Administration's (FDA)behest, to propose standards for mechanical calibration that would replace thetraditional USP performance verification test (PVT) using standard prednisonetablets. The FDA concluded that "sole reliance upon reference standard tabletsto evaluate the performance of USP Dissolution Apparatus 1 and 2 does notprovide assurance that the apparatus is adequately calibrated as required byCGMP regulations. Enhanced MC is advantageous, enabling a dissolution apparatusoperator to minimize the significant sources of measurement system variationidentified in the recently published studies."
Well, maybe, concludes Bryan Crist, manager of scientificservices for Agilent Technologies' dissolution systems operation in Cary, N.C.Crist cut his dissolution teeth, as it were, at VanKel Technologies underthen-owner and dissolution pioneer Jim Swon, and has continued studying the artand science, first with Varian Inc. which bought out Swon, and then Agilentafter the latter acquired Varian. He has pointed out a number of areas wherethe ASTM/FDA guidelines leave important questions unanswered.
While there have been many perturbation studies, he notes,they have all focused on a single variable and inducing enough change to causea failure—ironically, using the USP calibrators as the standard. What is notyet understood is the cumulative impact of all these variables, which could beenough to fail a good batch—or worse, fail to catch a bad one.
There areseveral factors that should provide sufficient justification to maintain thepresent performance verification system with the USP calibrator tablets until furtherstudies have been conducted and changes have been made to ensure the mechanicalintegrity of the dissolution system and its environment, Crist believes.
Factor #1: Vibration
At this time, vibration is not well understood and is notconsistently quantified. The impact on higher dissolution release rates due tovibration is widely known and has been the source of aberrant dissolution data.The PhRMA Subcommittee on Dissolution Calibration agrees, having stated that"it appears that some type of calibrator tablet should be maintained untilenhanced mechanical calibration establishes a definitive vibration tolerance."
Factor #2: Vesselgeometry
Vessels are one of the most critical factors for propercontrol of a dissolution system, and their impact goes beyond calibrationalone. Vessel dimensions and orientations greatly affect vessel hydrodynamics,tablet positioning and reproducibility of data between positions.
AgilentTechnologies has introduced a TruAlign vessel, which the company claims hasseveral advantages compared to a traditional dissolution vessel, to ensure themost accurate and reproducible results.
The TruAlign glass vessel is manufactured on a lathe toguarantee proper centering of the vessel in the vessel plate. Further, thecollar fits horizontally in the vessel plate and locking tabs hold the vesselperfectly vertical to minimize any vessel movement during the run.
Crist also points out that the only specifications given forthe dissolution vessel are height and inner diameter. Checking vesselconformance with fingertips to detect deformities and irregularities of one ofthe most critical components of the dissolution environment is not goodscience, he says. There is no consideration for an actual hemispheric toleranceor overall condition of the vessels, including shape, cracks, pits, scratchesand residue. Each of these things has been investigated and identified as thesource of calibration failures in the past.
"How will they be accounted for without specifications or aholistic test with calibrator tablets?" he asks.
Factor #3: Cumulativeperturbation
All of the perturbation studies to date have been performedin terms of tuning a dissolution apparatus as close to perfect as possible andvarying one parameter at a time to study its effect. If many of the mechanicalparameters are near the limit of their tolerance, what will be the effect onthe dissolution rate?
The ideal dissolution environment is a quiet,symmetrical, smoothly rotating system. If vessel asymmetries, presence of vibration,wobble, temperature and spindle height are within tolerance but near the limit,would they not have a cumulative effect on dissolution rates?
Modeling softwareexists, Crist notes, which might help predict the effect of multiple variableson the dissolution test. This is an area that needs further research toascertain the usefulness of this type of tool, he believes.
Martin and Crist are among the 40-plus members of the InVitro Release and Dissolution Testing Focus Group, which surveyed its members inNovember 2009 and learned that about two-thirds currently use the USPPerformance Verification Test (PVT), while about one-quarter were performingmechanical calibration only per FDA guidelines. Almost half of the respondentswere waiting on the FDA to make a decision on the acceptability of mechanicalcalibration only. In terms of vibration, 50 percent still use the sense oftouch to evaluate whether or not they have achieved the ideal of "a quiet,symmetrical, smoothly rotating system."
The Holy Grail: IVIVC
IVIVC has been defined by the FDA as "a predictive mathematical modeldescribing the relationship between an in-vitroproperty of a dosage form and an in-vivoresponse."
Generally, the in-vitro propertyis the rate or extent of drug dissolution or release, while the in-vivo response is the plasma drugconcentration or amount of drug absorbed.
The USP also defines IVIVC as "the establishment of a relationship between abiological property, or a parameter derived from a biological property producedfrom a dosage form, and a physicochemical property of the same dosage form."Typically, the parameter derived from the biological property is AUC or Cmax, while thephysicochemical property is the in-vitrodissolution profile.
The goal of developing reliable means for routine IVIVC determinations is touse the dissolution test as a surrogate for human studies. Such analytical datafrom drug dissolution testing can also be sufficient in many cases to establish safety and efficacy of a drug productwithout in-vivo tests, followingminor formulation and manufacturing changes. Thus, the dissolution testingwhich is conducted in dissolution apparatus must be able to provide accurateand reproducibleresults.
But as is true of all dissolution measurements of drug release, "one swallowdoes not a summer make." As Martin points out, for an "A" level correlation youneed three formulations with point-to-point plasma and dissolution time pointsthat correlate, which has not proven to be easy—or even possible—in many cases.
The DissolutionDiscussion Group
Founded more than 12 years ago by then VanKel Technologiespresident Jim Swon, the Dissolution Discussion Group (DDG) was one of the earlyInternet user forums, notes Andrew Damon, who has monitored discussions formuch of the group's history. The DDG provides scientists and technicians withthe opportunity "to participate in vendor-neutral online forum discussions onindustry research, best practices, regulatory issues, R&D challenges andmore in an environment that is free from regulatory oversight."
According to Damon, discussion threads that are currently ofparticular interest are PVT testing using a new prednisone lot and dealing withUSP vessel centering specifications.
