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Drug delivery: Why getting there isn’t half the fun
Tablets, capsules, the "pink medicine" that sits on refrigerator shelves to help nurse small children with sore throats and ear infections—and now more exotic formulations such as transdermal patches and medicated stents—all must be rigorously tested to ensure that they actually deliver the active pharmaceutical ingredient as promised. And delivery is much less a sure thing than it was in the past, says Greg Martin, president of Complectors Consulting and a widely acknowledged expert in the field.
For more than 30 years, Martin has applied his knowledge and experience to solving the ongoing riddles that frequently bedevil drug delivery. He points out that the dissolution method is important because it is the only in-vitro test that addresses product availability. It is a primary quality control test that all products must pass to be on the market. With evolving dosage forms, the dissolution test (or what might be called the in-vitro release test) is constantly being improved or changed with newer equipment and methods.
In terms of solubility, "we've harvested most of the low-hanging fruit," Martin says.
In most categories, effective drugs already exist. To develop new drugs to replace them, researchers search out exotic molecules that are almost always less soluble. Poor solubility may account for 60 to 90 percent of the small molecules for oral administration now in development, with solubility 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 surfactant solutions such as sodium lauryl sulfate or a commercial product called Tween 80. Some drug developers are experimenting with ligands such as polysaccharides, while others are exploring the use of surfactants as part of the drug formulation, all aimed at dealing with poor inherent solubility.
Setting appropriate specifications for the test is a challenge for the industry and the regulatory agencies. Harmonization of the dissolution test is an ongoing point of discussion, as is the calibration of the equipment. The goal of relating the in-vitro test to in-vivo drug pharmacokinetic data is still a centerpiece for many discussions concerning the ability of the test to predict bioequivalence.
Traditionally, dissolution methods have been developed as quality control tests, Martin notes. More recently, biorelevant dissolution has been 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 or post-approval changes or to obtain biowaivers when introducing a lower potency, he observes. Hence, it is important to identify the purpose before developing a dissolution method.
"What type of dosage form will be tested? Test conditions for an immediate release product will be different from those for an extended release or delayed release product, and the apparatus used for a tablet might be different from one used for a transdermal patch or medicated stent," Martin says.
Martin notes that two types of test apparatus dominate the technology: U.S. Pharmacopeial Convention (USP) Apparatus 1 and 2—with 2, which involves dropping the dosage form into a dissolution vessel and stirring the medium with a paddle, being the most popular. Apparatus 1 uses a mesh basket that contains the dosage form in place of the paddle. In both cases, samples are withdrawn from the vessel at regular periods using UV-visible spectroscopy or HPLC. Fiber-optic probes, resident in situ in the vessel, send the signal directly to the spectrometer.
A distant third in popularity—at least in the United States—is Apparatus 4, in which a constant flow 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 system that has been designed to overcome potential challenges linked to method development for a variety of dosage forms.
Stents are one such challenge, since they are designed to release products over a period of months. With the flow-through cell, fresh media passes continuously across the dosage form in an open loop system. A semi-automated system allows samples to be taken simultaneously and collected in a fraction collector or analyzed directly by UV. Dissolution can also be analyzed in situ in a fiber-optic dissolution system.
Tests using both Apparatus 1 and 2 have been the subject of an abiding controversy occasioned by the American Society for Testing and Materials (ASTM) stepping in, at the U.S. Food and Drug Administration's (FDA) behest, to propose standards for mechanical calibration that would replace the traditional USP performance verification test (PVT) using standard prednisone tablets. The FDA concluded that "sole reliance upon reference standard tablets to evaluate the performance of USP Dissolution Apparatus 1 and 2 does not provide assurance that the apparatus is adequately calibrated as required by CGMP regulations. Enhanced MC is advantageous, enabling a dissolution apparatus operator to minimize the significant sources of measurement system variation identified in the recently published studies."
Well, maybe, concludes Bryan Crist, manager of scientific services for Agilent Technologies' dissolution systems operation in Cary, N.C. Crist cut his dissolution teeth, as it were, at VanKel Technologies under then-owner and dissolution pioneer Jim Swon, and has continued studying the art and science, first with Varian Inc. which bought out Swon, and then Agilent after the latter acquired Varian. He has pointed out a number of areas where the 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 cause a failure—ironically, using the USP calibrators as the standard. What is not yet understood is the cumulative impact of all these variables, which could be enough to fail a good batch—or worse, fail to catch a bad one.
There are several factors that should provide sufficient justification to maintain the present performance verification system with the USP calibrator tablets until further studies have been conducted and changes have been made to ensure the mechanical integrity of the dissolution system and its environment, Crist believes.
Factor #1: Vibration
At this time, vibration is not well understood and is not consistently quantified. The impact on higher dissolution release rates due to vibration 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 until enhanced mechanical calibration establishes a definitive vibration tolerance."
Factor #2: Vessel geometry
Vessels are one of the most critical factors for proper control of a dissolution system, and their impact goes beyond calibration alone. Vessel dimensions and orientations greatly affect vessel hydrodynamics, tablet positioning and reproducibility of data between positions.
Agilent Technologies has introduced a TruAlign vessel, which the company claims has several advantages compared to a traditional dissolution vessel, to ensure the most accurate and reproducible results.
The TruAlign glass vessel is manufactured on a lathe to guarantee proper centering of the vessel in the vessel plate. Further, the collar fits horizontally in the vessel plate and locking tabs hold the vessel perfectly vertical to minimize any vessel movement during the run.
Crist also points out that the only specifications given for the dissolution vessel are height and inner diameter. Checking vessel conformance with fingertips to detect deformities and irregularities of one of the most critical components of the dissolution environment is not good science, he says. There is no consideration for an actual hemispheric tolerance or overall condition of the vessels, including shape, cracks, pits, scratches and residue. Each of these things has been investigated and identified as the source of calibration failures in the past.
"How will they be accounted for without specifications or a holistic test with calibrator tablets?" he asks.
Factor #3: Cumulative perturbation
All of the perturbation studies to date have been performed in terms of tuning a dissolution apparatus as close to perfect as possible and varying one parameter at a time to study its effect. If many of the mechanical parameters are near the limit of their tolerance, what will be the effect on the 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 software exists, Crist notes, which might help predict the effect of multiple variables on the dissolution test. This is an area that needs further research to ascertain the usefulness of this type of tool, he believes.
Martin and Crist are among the 40-plus members of the In Vitro Release and Dissolution Testing Focus Group, which surveyed its members in November 2009 and learned that about two-thirds currently use the USP Performance Verification Test (PVT), while about one-quarter were performing mechanical calibration only per FDA guidelines. Almost half of the respondents were waiting on the FDA to make a decision on the acceptability of mechanical calibration only. In terms of vibration, 50 percent still use the sense of touch 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 model describing the relationship between an in-vitro property of a dosage form and an in-vivo response."
Generally, the in-vitro property is the rate or extent of drug dissolution or release, while the in-vivo response is the plasma drug concentration or amount of drug absorbed.
The USP also defines IVIVC as "the establishment of a relationship between a biological property, or a parameter derived from a biological property produced from 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 the physicochemical property is the in-vitro dissolution profile.
The goal of developing reliable means for routine IVIVC determinations is to use the dissolution test as a surrogate for human studies. Such analytical data from drug dissolution testing can also be sufficient in many cases to establish safety and efficacy of a drug product without in-vivo tests, following minor formulation and manufacturing changes. Thus, the dissolution testing which is conducted in dissolution apparatus must be able to provide accurate and reproducible results.
But as is true of all dissolution measurements of drug release, "one swallow does not a summer make." As Martin points out, for an "A" level correlation you need three formulations with point-to-point plasma and dissolution time points that correlate, which has not proven to be easy—or even possible—in many cases.
The Dissolution Discussion Group
Founded more than 12 years ago by then VanKel Technologies president Jim Swon, the Dissolution Discussion Group (DDG) was one of the early Internet user forums, notes Andrew Damon, who has monitored discussions for much of the group's history. The DDG provides scientists and technicians with the opportunity "to participate in vendor-neutral online forum discussions on industry research, best practices, regulatory issues, R&D challenges and more in an environment that is free from regulatory oversight."
According to Damon, discussion threads that are currently of particular interest are PVT testing using a new prednisone lot and dealing with USP vessel centering specifications.