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á1001ñ IN VITRO RELEASE TEST METHODS FOR PARENTERAL DRUG
PREPARATIONS
INTRODUCTION

Parenterally administered drugs include injections that are administered through the external boundary tissue with
subsequent immediate release or extended release of the drug substance into the circulatory system. Parenteral drugs also
include drug preparations that are administered by placement within the body to achieve, for instance, extended release of
drug substance at a local area. Immediate and modified-release parenteral drug products exist as injections (solutions,
suspensions, emulsions) and implants. Immediately prior to administration, the parenteral drug preparation may be
reconstituted from sterile powders to form solutions, suspensions, or emulsions. Such parenteral drug preparations also include
drug/device combinations such as stents. Generally, performance tests, as discussed in this chapter, are not required for aqueous
solutions.
The definitions and descriptions of dosage forms and drug preparations discussed in this chapter, as well as information
about their composition and manufacturing processes, can be found in Pharmaceutical Dosage Forms á1151ñ.
The intention of á1001ñ is to provide guidance on methods that have been demonstrated as useful for the evaluation of
product release performance testing of parenteral drug preparations. When reference is made to “dissolution”, “in vitro release”,
“in vitro drug release”, “drug release”, and “performance” in this chapter, these terms are intended to have the same meaning.

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This chapter is not intended to establish new testing requirements for parenteral drug preparations.

COMMON PRINCIPLES
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For parenteral dosage forms and parenteral drug preparations, the purpose of both the product quality tests and product
performance tests is to assure batch-to-batch quality, reproducibility, reliability, and performance. Product quality tests are
performed to assess attributes such as assay, identification, impurities, foreign particulate matter, sterility, bacterial endotoxins,
water content, aluminum content, and content uniformity. These tests are part of the compendial monograph (see Injections
and Implanted Drug Products á1ñ). Method selection can be challenging for many reasons, and each preparation carries its own
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unique obstacles. The Dissolution Procedure: Development and Validation á1092ñ is an important reference to use when developing
an in vitro release test procedure. It is advisable to consult with the appropriate regulatory agency to confirm the adequacy of
an in-house in vitro drug release test for a drug product before filing the application.
The drug release test method should be developed early in product development so it can be used to characterize the
preparations utilized in safety and efficacy trials. The drug release data for the batches used in these studies support the
specifications for the drug release test at product release and expiry. Furthermore, it is important to coordinate the in vitro drug
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release method strategy for product development with the quality control (QC) method for release of the product. This strategy
is useful in product life-cycle management to support possible manufacturing changes.
Each type of parenteral dosage form or preparation is discussed in this chapter, including highlights of the preparation’s
unique challenges. Examples of methods for current preparations are provided; these examples come from multiple sources
including, but not limited to, the Food and Drug Administration’s Dissolution Methods Database (1), workshop reports (2–3),
Pharmacopeial Forum articles (4–6), and other scientific literature. For several parenteral drug preparations, procedures
described in Dissolution á711ñ, Drug Release á724ñ, Mucosal Drug Products—Performance Tests á1004ñ, or Semisolid Drug Products
—Performance Tests á1724ñ may be applicable.
The FDA’s Dissolution Methods Database currently includes several injections and performance test methods for injectable
suspensions. When a specific method is not given in this database, the instructions state, “Develop a dissolution method using
USP 4 (Flow-Through Cell), and, if applicable, Apparatus 2 (Paddle) or any other appropriate method, for comparative evaluation
by the Agency.” The injectable suspensions with methods provided use USP Apparatus 4 and 2, and the test media may include
sodium lauryl sulfate (SLS), polysorbate, saline, water, and a small amount of ethanol. The testing time ranges from 45 min to
as long as 168 h. Accelerated in vitro release test conditions may be necessary if a performance test method serves as a drug
product QC tool as long time frames are generally not practical.
There are many types of extended-release parenteral drug products commercialized in the veterinary industry. The FDA’s
Center for Veterinary Medicine (CVM) Guidance for Industry #238, provides guidance and strategies for consideration as part
of the development program for drug release testing and product specifications (7).
Because of the complex nature of some parenterals, in vitro drug release test methods should be applied on a case-by-case
rather than one-size-fits-all basis; however, the inclusion of general approaches and the presentation of options can be useful.
Some parenteral drug preparations provide continuous release of the drug substance(s) for weeks, months, or years. The in
vitro release test conditions can, although they are not required to, mimic specific aspects of the intended physiological
environment such as the osmolarity, pH, or buffer capacity. Non-sink conditions may be informative in some instances (sink
conditions are defined in á1092ñ). The composition of the drug-release media may be kept constant with regard to the
physiological parameters for pH (e.g., pH 7.4) and osmotic pressure (e.g., 285 mOsm/kg). Because of the solubility of the drug
substance and the requirement for an accelerated test, the addition of surfactants (e.g., polysorbate 80 or SLS) and/or organic
solvents may be needed. Accelerated in vitro release testing is a practical solution for QC testing; however, it should be justified
as having relevance. This is historically established through clinical trial data along with patient use and may be tied to product
attributes that are controlled through validated manufacturing parameters (e.g., excipient quality and preparation, mixing, and
time conditions) and batch release testing.

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It is well known that the in vitro release of a drug from a drug product is preparation dependent. Therefore, it is unlikely a
universal in vitro release test method can be designed to characterize drug release for the wide variety of existing parenteral
dosage forms and preparations that exist. Assessing the suitability of a method for a preparation is therefore crucial.
Characteristics of an in vitro drug release test for parenteral drug preparations may include, but are not limited to, the
following:
• Distinguishes a compliant batch [where a compliant batch is bioequivalent (BE) to the pivotal batches]
• Mimics the drug release conditions in vivo
• Utilizes early sampling to characterize the initial release
The performance test method may need to discriminate the critical quality attributes, which may include initial release; and
any material, process, or product attribute that affects the subsequent release rate. In vitro release testing should be conducted
with parenteral drug preparations that are manufactured under target conditions then compared to drug products that are
intentionally manufactured with critical attribute variations in preparation and manufacturing parameters (8–9).
Multiple components/manipulations make up the drug release methods and are reported in the literature, and their
associated equipment (or apparatus), are summarized in Table 1 (10).

Table 1. Examples of Equipment and Techniques that Could be Incorporated into a Drug Release Method
Techniques Continuous Sampling Unique Advantages Limitations
Dialysis membrane, rather than the
preparation, may be rate limiting;
Dialysis Yes Filtration usually not required nonspecific membrane adsorption
Dialysis membrane, rather than the

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Filtration usually not required; direct preparation, may be rate limiting;
Reverse dialysis/microdialysis Yes measurement with microdialysis nonspecific membrane adsorption
Preparation dependent; sample may
not be resuspendable; nonspecific
Centrifugation No ci Filtration not required membrane adsorption
Centrifugal filtration No Low centrifugal force possible Filter clogging/particle deformation
Pressure ultrafiltration No Gentle separation at low pressure Filter clogging/particle deformation
Size-exclusion chromatography Yes Selection of filter media Column presaturation needed
In situ method (fiber optics) Yes Direct measurement Polarography and UV/Vis limited
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Continuous flow method Yes Flexible media volume Filter clogging
Filter clogging/potentially high vol-
USP Apparatus 4 Yes Flexible media volume ume of release media
Defined maximum and minimum vol-
USP Apparatus 1 Yes Well-characterized equipment ume
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Defined maximum and minimum vol-

USP Apparatus 2 Yes Well-characterized equipment ume

The drug release test for some parenteral dosage forms may require the use of modified compendial or noncompendial
equipment. For example, various volumes of dissolution media with or without agitation may be appropriate. The use of a
dialysis membrane as well as the use of incubation methods have been shown to be beneficial for some preparations. Table 2
provides known examples of suitable apparatus for types of preparations.

Table 2. Known Examples of Apparatus Used for In Vitro Release for Parenteral Preparations
Preparations Apparatus
Nonaqueous solutions/oily preparations Apparatus 2

Suspensions Apparatus 2, Apparatus 4, reduced volume apparatus, dialysis cell

Nanosuspensions Apparatus 2, Apparatus 4, dialysis cell, reduced volume

Liposomes Apparatus 1, Apparatus 2, Apparatus 4, dialysis cell

Microparticles Apparatus 2, Apparatus 4, incubation jar, dialysis cell

Powders for suspension Apparatus 2, Apparatus 4, reduced volume apparatus, dialysis cell

Emulsions Apparatus 2, reduced volume apparatus, vertical diffusion cell

Implants Apparatus 2, Apparatus 4, Apparatus 7, incubation jar

Drug-eluting stents (DES) Apparatus 7, Apparatus 4, modified flow-through cell

In-situ forming preparations Apparatus 2, Apparatus 4, Apparatus 7, incubation jar

When long-term in vitro release tests are needed, special attention should be paid to the evaporation of the test media,
microbial growth, and chemical degradation of the released/dissolved drug as discussed below:
• Evaporation: Sealed containers (e.g., jars or vials) and Apparatus 4 help prevent test media evaporation. Where justified,
it may be possible to include an internal standard to correct for test media volume changes due to evaporation. An

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appropriate internal standard would be chemically stable, nonvolatile, and possess suitable chromatographic or spectral
properties so that it can be quickly and reliably quantified independently of the active ingredient. If a poorly sealed
apparatus is used for real-time tests (e.g., Apparatus 2) with an internal standard, consideration should be given to whether
the reduction in volume over time will affect the sink conditions of the test media.
• Microbial growth: Microbial growth may be limited by using preservatives in the test media. Concentrations between
0.1% and 0.01% w/v sodium azide are reported in the literature (11–12). It should be noted that sodium azide is toxic
to humans and may be a carcinogen, so alternative antimicrobials should be considered.
• Chemical degradation: Degradation of the released or dissolved drug in the test media may be partially or wholly
addressed by using a nonspecific measurement technique such as UV-Vis spectroscopy, HPLC with class separation (the
drug and all solution-phase degradants coelute), or summing of all drug-related peaks (with appropriate justification). The
latter approach is predicated on the common observation that solution-phase chemistry tends to be much faster than
solid-phase. In other words, the drug likely degrades after dissolution, so summing all degradation products and the parent
compound in solution is likely a good indication of the quantity of drug that dissolved. In some cases, the addition of an
antioxidant to the dissolution media or the use of an alternate pH where the drug is more stable may also be useful. Lastly,
the use of Apparatus 4 in open loop mode may help mitigate degradation, because a dissolved drug does not remain in
the system for the duration of the test, but open loop may create challenges for detection sensitivity.
In the case of accelerated in vitro release methods, many of the same considerations described above apply, i.e., elevated
temperature can promote evaporation and chemical degradation.
Although desirable, in vitro and in vivo correlations may not be possible for modified-release parenteral dosage forms due
to the complexity of the release mechanisms and the lack of knowledge about in vivo release conditions. However, the in vitro
release method should reflect the route of administration. An in vitro drug release method with proven IVIVC potential would
have a long-term advantage in terms of serving as a surrogate for in vivo BE testing required to qualify higher level scale-up

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and post approval changes for modified release (SUPAC-MR).
The following sections provide performance test guidance that is unique to parenteral dosage forms and parenteral
preparations discussed in this chapter.

SOLUTIONS
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One recent example reported by Priddy et al. describes the work conducted for a veterinary drug product consisting of a
lipophilic drug dissolved in a low-viscosity oily matrix (13). This publication describes important considerations such as the
identification of a suitable medium that dissolves the drug over time without degrading it and the development of a system
and methodology that can be used as a QC lab tool and as a way to discriminate a quality drug product from one that was
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formulated or processed incorrectly.

SUSPENSIONS

Suspension dosage forms are solids suspended in a suitable liquid. Examples of suspensions include liposomes, microparticles,
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poorly water-soluble drug substances, and drug substances deliberately formulated to achieve prolongation of their release
compared to that observed or anticipated for an immediate-release dosage form. Nanosuspensions consist of solids with any
dimension inside and outside the nanoscale range of 1–100 nm but with properties attributed to its dimension (less than
1000 nm), suspended in a suitable liquid, typically water with other components (6,14–15 and Drug Products Containing
Nanomaterials á1153ñ).
The FDA provides guidance on in vitro performance testing of modified-release parenteral dosage forms and drug
preparations containing nanomaterials (14). Ideally in vitro drug release testing should be performed using compendial
instruments described in á711ñ and á724ñ. However, use of compendial instruments is not required.
Determination of the test media composition is the first key step to setting up an in vitro performance test (e.g., choice of
organic solvent(s), surfactant, buffer, and pH).
Addition of the suspension test article to the test vessel or cell is another key step. For example, addition of suspension test
articles into the test media may significantly alter the inherent drug release and/or dissolution characteristics of the suspension
depending on the composition and volume of the test media and how the suspension test article is diluted prior to dissolution.
Another key step is sampling from the test media, including separating the test article from the dissolved drug (16). Many
isolation techniques are employed to separate the test article from the released drug. Two major filtration technologies are used
to isolate test samples. One is dead-end filtration, where particles are collected on the surface of the filter device. The second
type of filtration is cross-flow filtration, where the suspension flows across the surface of a membrane filter with minimal particle
buildup on the filter. Filters with a particle pore size smaller than 100 nm may be considered. In situ fiber optics combined with
derivative spectroscopy allow quantification of the dissolved drug substance in the presence of the bound or encapsulated drug
substance associated with the nanoparticle (17–18).
Compendial instruments with a basket, paddle, or flow-through cell can accommodate a bag or pouch (e.g., dialysis tubing
clamped at both ends) that contains the suspension test article. The bag or pouch can consist of a dialysis membrane with a
defined molecular weight cut-off. Another dialysis technique (known as reverse dialysis) uses a dialysis bag or pouch with only
test media inside. This pouch is placed in the test media containing the suspension test article. Samples of released drug are
taken from inside the pouch. This technique allows for placement of test article in the bulk media to, for example, minimize
the agglomeration and aggregation effects.
Nanosuspensions or suspensions can be deliberately formulated to prolong or accelerate the rate of release of a drug based
on the poor water solubility of the drug and on the in vivo diffusion dynamics of the drug in the biological fluid or matrix. In
such cases, dissolution of the suspension in a typical performance testing apparatus may be very rapid. The provision of full
solubility is typically required in order to meet regulatory expectations (able to meet Q = 80, for example), and biologically

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relevant diffusion barriers are difficult to construct. For such suspensions, the most likely product attribute for which the
performance test must discriminate (most likely to affect pharmacokinetics) may be the specific surface area (SSA) of the drug
substance particles, for which drug substance particle size is often a good surrogate. As such, any in vitro release test that
measures the impact of variations in SSA or particle-size distribution may be appropriate for performance control, regardless of
the speed of dissolution. Consideration should also be given as to whether a direct measurement of particle size (e.g., via light
scattering) may be a better measurement of likely in vivo product performance.

LIPOSOMES

Liposomes are submicron to micron-sized vesicles composed of a single lipid bilayer surrounding an aqueous core or a
concentric series of multiple bilayers separated by aqueous compartments. The bilayers are formed by amphipathic molecules,
such as phospholipids and cholesterol. Generally, liposome drug products comprise the drug substance and lipid components,
as well as non-lipid inactive ingredients.
In liposomal drug products, the drug substance can be encapsulated within the aqueous compartment(s) [hydrophilic drugs]
, intercalated within the lipid bilayer(s) [hydrophobic drugs], or associated with the surface(s) of lipid bilayer(s) [charged and/
or amphiphilic drugs]. Drug release is not a consequence of dissolution of the liposomes. It is dependent on a combination of
factors including the following:
• Lipid composition
• Nature of the drug (hydrophilic, hydrophobic, charged or uncharged)
• Location in the liposomes
• Molecular state (e.g., precipitated in the aqueous compartment or independent from environmental factors such as pH,

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counter ions, etc.)
• Liposome manufacturing/drug loading process (can affect the molecular state of the drug as well as the state of the
bilayer)
In vitro drug release testing is performed to characterize the functionality of the lipid bilayer. Such drug release testing can
also test for uncontrolled leakage (“dose-dumping”). In vitro release test conditions are chosen to discriminate changes that
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can occur in the drug product (the state of the lipid bilayer or the associated drug) during manufacturing or storage or in vivo.
In vitro drug release tests are used for lot release and stability testing. Examples of in vitro release techniques include
flow-through cells with dialysis membranes (USP Apparatus 4) and other dialysis methods. Furthermore, separation methods,
such as ultracentrifugation or filtration, can be employed.
Development of in vitro drug release assays can be challenging due to the complex dependence of release on the specific
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nature of the liposome preparation and drug. Standardized in vitro release techniques do not exist. Existing guidance documents
refer to specific drug products on the market. An FDA guidance document on chemistry, manufacturing, and control (CMC)
aspects of liposomes is available (19). At present, developers of liposomal drug preparations have proprietary in vitro drug
release methods for use in the QC of their preparations. More collaborative efforts among academia, industry, and regulators
are needed to standardize in vitro drug release testing of liposomes (20).
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MICROPARTICLES

Microparticles, or microspheres, ( á1151ñ) are larger than 100 nm and are typically incorporated into suspensions for injection.
Often microparticles are powders containing extended-release particles that just prior to administration are suspended in a
suitable liquid. There are two distinct challenges when performing an in vitro drug release test on microparticles. First, if
microparticles do not wet well, as observed by floating or aggregating, then the test media can be modified by adding a small
quantity of surfactant to the media to reduce the surface tension. Secondly, microparticles may require a prolonged testing
time, which could cause extensive evaporation of the dissolution media and chemical degradation of the released drug in the
media. See the Common Principles section on chemical degradation for additional recommendations. Methods that use dialysis
membranes with microparticles have been reported in the literature (21).

EMULSIONS

For emulsions, the drug substance is typically trapped within a water-in-oil or oil-in-water dispersed phase; however, the
majority of parenteral emulsions are oil-in-water emulsions. When assessing the drug release of these type of emulsions, the
apparatus described in á711ñ, á1004ñ, and á724ñ may be appropriate; these apparatus include USP Apparatus 2, dialysis cell,
USP Apparatus 4, a vertical diffusion cell, and reduced-volume equipment.

IMPLANTS

For extended-release implants, the in vitro drug release test should include a procedure to ascertain whether the drug releases
as intended and to prove the robustness of the drug product. There may be a regulatory expectation for real-time (long-term)
in vitro drug release tests used along with accelerated in vitro drug release tests. Some acceleration strategies include elevated
temperatures, non-neutral pH to increase the hydrolysis of rate-controlling polymers and/or to increase the drug solubility, and
organic cosolvents used to increase drug solubility and/or to increase the permeability of rate-controlling polymers. Both
real-time and accelerated performance tests should be well studied and justified in their predictive ability (clinical relevance)
and/or discriminatory power for QC.

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In the USP monograph Goserelin Implants, the apparatus is a sealed jar that is incubated. Apparatus 4 and Apparatus 7 are
also used (5–8). The FDA database provides three implant methods: the goserelin implant uses an incubation method, the
dexamethasone implant uses Apparatus 7, and the buprenorphine hydrochloride implant uses Apparatus 2.

DRUG-ELUTING STENTS

Drug-eluting stents (DES) are a combination of a device and a drug, where the drug is usually within a polymeric matrix that
coats the stent. As with implants and extended-release microparticle suspensions, the long-acting nature of the DES makes long
in vitro release tests (up to 6 months in some cases) necessary to fully characterize the drug release profile. Long tests come
with the challenges of media evaporation and stability of drug substances within the media. The possibility of accelerated
conditions is an important consideration, as the in vivo release may occur over a long period of time. Other considerations are
the positioning of the DES in the apparatus for adequate mixing and the use of a small volume of media due to the low drug
concentration.
There are performance test methods suggesting the use of a reduced-volume paddle apparatus—USP Apparatus 4 or USP
Apparatus 7 with stent holders—where small volumes of media are used (4). For the approved DES, sirolimus, USP Apparatus
4 (flow rate of 25 mL/min) was used with an elution media (50 mL) of 2% SLS and 10% acetonitrile at a pH of 4.5 and a
temperature of 37° (22). This is a closed-loop configuration.
The method needs to reflect the transport forces that are predominant in vivo (23). This has been demonstrated in methods
using a blood vessel-simulating flow-through cell apparatus (24). Other apparatus that have been used for in vitro drug release
testing of DES are as follows: incubation cells of different volumes, agitation at 250–300 rpm at 37°, and USP Apparatus 7 with
small-volume reciprocating holders in 10-mL glass cells at dip rates of 5 or 40 DPM (25).

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1. Food and Drug Administration. Dissolution Methods Database. https://www.accessdata.fda.gov/scripts/cder/

dissolution/index.cfm. Accessed 07 Jan 2020.
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2. Burgess D, Hussain A, Ingallinera T, Chen M. Assuring quality and performance of sustained and controlled released
parenterals: AAPS Workshop Report, Co-Sponsored by FDA and USP. Pharm Res. 2002;19(11):1761–1768.
3. Brown C, Friedel H, Barker A, Buhse L, Keitel S, Cecil T, et al. FIP/AAPS joint workshop report: Dissolution/in vitro release
of novel/special dosage forms. AAPS PharmSciTech. 2011;12(2):782–794.
4. Shah V, DeMuth J, Hunt D. Performance tests for parenteral dosage forms. Pharm Forum. Rockville, MD: USP; 2015;41(3).
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5. Burgess D, Clarke B, Hampson-Carlin M, Shah P. Critical quality and performance parameters for modified-release
parenteral dosage forms. Pharm Forum. Rockville, MD: USP; 2005;31(6).
6. Joint Subcommittee of the USP Expert Committees on Dosage Forms, Physical Analysis, and Chemical Analysis. Stimuli
to the revision process: Drug products containing nanomaterials. In Pharm Forum. Rockville, MD: USP; 2017;43(3).
7. US Food and Drug Administration, Center for Veterinary Medicine. Guidance for industry #238. Modified release
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veterinary parenteral dosage forms: development, evaluation and establishment of specifications. June 2016. https://
www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM481721.pdf.
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development: challenges and regulatory perspective. AAPS J. 2017;19(6):1669–1681.
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human pharmacokinetics and bioavailability; and labeling documentation. April 2018.

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DOI Ref: m1cpr DOI: https://doi.org/10.31003/USPNF_M5433_02_01
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20. Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications,
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Pharm Sci. 2000;1(1):30–40.
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Dissolut Technol. 2011;18(4):37–42.
23. Seidlitz A, Weitschies W. In vitro dissolution methods for controlled release parenterals and their applicability to drug
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