Pharmaceutical Formulation

AFA® powered drug formulation systems can improve a variety of pharmaceutical formulations. From early-stage discovery processing to continuous flow manufacturing with PAT feedback, AFA processing can dramatically shorten processing time, improve reproducibility, and construct formulations that are otherwise not possible.

AFA Technology for Pharmaceutical Formulation and Drug Delivery

Today, the majority (> 80%) of new chemical entities (NCE) discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds; as are about 40% of existing drugs in the market. Consequently, this creates major challenges in drug development due to poor solubility, short biological half life, poor bioavailability, prominent adverse effects, and stability of NCE.
Adaptive Focused Acoustics® (AFA®) provides the ability to process a number of different constructs to help overcome solubility difficulties. Using AFA-based systems, both Liposomes and Emulsions are prepared at low processing temperatures without the use of organic solvents. This allows for the encapsulation of temperature or solvent sensitive APIs such as peptides or proteins, which would otherwise be destroyed or inactivated during the preparatory processing. Thus, API’s previously considered not feasible, can now be considered for development.

Download the Formulations Brochure

FEATUREBENEFIT
IsothermalEliminates molecular thermal damage by maintaining isothermal sample temperatures during the process
ScalableScales from bench-top screens through clinical studies (microliters to 1,000+ liters)
Compatible with Quality By Design and Process Analytical Technology
Non-contactEnables sterile, closed, single-use fluid circuits which eliminate carryover Enables disposable wetted surfaces which minimizes impurities
ReproducibleStandardizes the process application of industry-proven AFA® technology Automated process by minimizing subjective operator influence
RapidImproves processing performance (from 2 days to 2 minutes);
increases solubility and stability

AFA Enabled Applications for Pharmaceutical Formulations and Drug Delivery Systems

Micronization

Reducing a suspensions particle size with micronization can help mitigate these effects. AFA can be used for particle size in a controlled manner to make uniform suspensions with low micron or nano-scale particle sizes.



Nanosuspension

Nanosuspensions have emerged as an effective strategy for the delivery of hydrophobic drugs because of the unique versatility and advantages in formulation. AFA can be used to create nanosuspensions through the complete life cycle from discovery through first human trials. By enabling closed vessel, contamination free wet milling in a scalable manner, early-stage compounds can be dosed and evaluated, without extensive Formulation development, with a very minimal amount of material. Subsequent trials can be completed with the same technology through the preparation of larger volumes of nanosuspension sample material.
The Covaris Focused Ultrasonicator has successfully demonstrated the ability to mill small volumes of early stage material into nanosuspensions suitable for animal dosing. Volumes as low as 100ul are possible with 100% recovery of the material.



SEM before and after wet milling

Crystallization

AFA can be used to control nucleation and crystal distribution. Other benefits of AFA technology for crystallization include:



Ibuprofen with AFA produces 700 nm particles while untreated samples are large, uneven clumps.

AFA-Liposome Formation

Liposomes are being used to deliver a number of different active pharmaceuticals for both small and large molecule API. Traditional liposome preparation methods include detergent depletion, ethanol injection, reverse-phase evaporation and emulsification. Processing methods include high-pressure homogenization, extrusion, and conventional ultrasound. The major disadvantages of these preparation methods include the consumption of large volumes of volatile organic solvents, multiple lengthy steps and degradation of the sample, and subsequent loss of bioactivity, due to heat exposure.
Adaptive Focused Acoustics® (AFA®) technology offers a breakthrough alternative to traditional methods, by forming monodisperse liposomes at 4°C (below the lipid phase transition temperature) and eliminating the need to use organic solvents.
Fully scalable from 100µL to continuous flow manufacturing, AFA-Liposome formation is possible across a range of lipids and formulations, including the addition of cholesterol and other difficult to load materials. Active ingredients can be loaded into the AFA-liposome at the time of formation, allowing a very simple and effective, one step formulation within a matter of minutes, without the risk of cross contamination or the need to cleanup.
FEATUREBENEFIT
Co-solvent freeNo need to dissolve lipids or hydrophobic compounds in a co-solvent. All the materials can be included in the aqueous buffer, and then formulated.
Low-Temperature FormulationLiposomes can be formed at 4°C, irrespective of the lipid phase transition temperature.
Delicate CompoundsEnergy levels can be pre-set to enable formulation of delicate macromolecules such as siRNA and proteins.
Short Processing TimeOne-step formulation using an automated apparatus.
No Cross ContaminationLiposomes are produced in single-use autoclavable vessels.
Automated Size Control (under development)Real-time monitoring and feedback control of particle size.
ScalableCapable of scaling from 100 µL to continuous flow manufacturing.

AFA-NANOPARTICLE® Formation (Polymer based)

Nanoparticles have been shown to be effective Drug Delivery Systems because of their biocompatibility and biodegradability. Nanoparticles act as potential carries for several classes of drugs such as anticancer agents, antihypertensive agents, immunomodulators, and hormones; and macromolecules such as nucleic acids, proteins, peptides, and antibodies.
AFA can be used in the emulsification steps of PLGA nanoparticle formation, to achieve monodisperse particle size distributions as small as 80nm. Additionally, the intense yet highly controllable mechanical energy of AFA allows the use of mild solvents, such as triacetin, in AFA-Nanoparticle formation. Combined with inherent low temperature processing, AFA-Nanoparticles are formed using temperature and solvent sensitive materials that would degrade with traditional processing methods.
As presented at CRS 2013 annual meeting in Honolulu: “Contact-free Encapsulation of Proteins in PLGA Nanoparticles by Focused Ultrasound” Schiller, et al.

AFA-Nanoemulsion Formulation

Nanoemulsions have become an important delivery system for the controlled delivery of pharmaceuticals and cosmeceuticals, and for the optimized dispersion of active ingredients in skin layers, as well as ocular delivery of active molecules.
AFA allows the construction of tightly distributed nanoemulsions achieving average mean particle sizes as low as 20nm. Volumes ranging from 100µL through continuous flow processing are possible, and all processing is done in a closed, sterile vessel at a controlled temperature. Tight temperature control enables the encapsulation of sensitive biological molecules such as peptides and proteins, without degrading bioactivity due to heating that alternative methods require.
Particle size and distribution can be controlled automatically via the acoustic processing parameters, to maintain a high quality output product.
TechnologyAFAMicrofluidizerSelf AssemblingSonication
HeatBelow room temp (<20°C)50-100°C60-100°CBased on time of exposure and power of sonication
Labor/SkillLowHighHighHigh
WastageLowHighMediumMedium
End productHomogenousHomogenousHomogenousNO
PressureNOHigh 24000-28000 psiNOBased on the time/power of procedure
Closed Vial ProcessYESNONONO
Cross contamination / ContaminationNOYESYESYES
Isothermal ProcessingYESNONONO
Precise Energy ControlYESNONONO
Non Contact processingYESNONONO
Heat damage to sampleNOYESYESYES
Repeatable without errorYESNONONO

Resources

References

Micronization

  1. Nano-suspension Formulations- Adaptive Focused Acoustics for the Formulation of Suspensions & Nano-Suspensions
    Authors: Srikanth Kakumanu, PhD, and Hames Bernhard. Published in Drug Development & Delivery | July/ August 2011 Vol 11 No6
  2. Technical Evaluation of Adaptive Focused Acoustics – Formulation solubility screening using AFA

Nanosuspension

  1. Poster Presentation GRC Preclinical Form and Formulation for Drug Discovery 2019: A DOE Approach for Nanosuspension Preparation for Poor Solubility Pharmaceutical Compounds Authors: Fenmei Zheng, Brian Michaels, and Yinqing Lin
  2. Poster Presentation AAPS 2012 Solidification of Nanosuspension via Spray Granulation.
    Authors: Yidan Lan, Srikanth Kakumanu, Carl Beckett, and Nigel Langley
    Demonstrated the feasibility of combining AFA technology (to produce nanosuspension by Tops down milling) and spray granulation.
  3. Nano-suspension Formulations- Adaptive Focused Acoustics for the Formulation of Suspensions & Nano-Suspensions
    Authors: Srikanth Kakumanu, PhD, and Hames Bernhard
    Published in Drug Development & Delivery | July/ August 2011 Vol 11 No6

Nanoparticle Formulation

  1. Contact-free Encapsulation of Proteins in PLGA Nanoparticles by Focused Ultrasound. Schiller, Hanefeld, Schneider, Weigandt, Lehr. 40th Annual Meeting and Exposition of the Controlled Release Society, July 21-24, 2013, Honolulu, Hawaii

Nanoemulsion Formation

  1. Contact-free Encapsulation of Proteins in PLGA Nanoparticles by Focused Ultrasound. Schiller, Hanefeld, Schneider, Weigandt, Lehr. 40th Annual Meeting and Exposition of the Controlled Release Society, July 21-24, 2013, Honolulu, Hawaii
  2. A simple, scalable, isothermal process for nanoemulsion formation. Kakumanu, Schmitt, He, Beckett, Laugharn. 40th Annual Meeting and Exposition of the Controlled Release Society, July 21-24, 2013, Honolulu, Hawaii